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Proposed
Preferred Drug List
with
Clinical Criteria
Proposal for TennCare
May 11, 2010
Page 1 of 52
February 18, 2010 Tennessee PAC
Responsibilities of the TennCare Pharmacy Advisory Committee
Source: Tennessee Code/Title 71 Welfare/Chapter 5 Programs and Services for Poor
Persons/Part 24 Tennessee TennCare Pharmacy Advisory Committee/71-5-2401 through 71-52404.



Make recommendations regarding a preferred drug list (PDL) to govern all state expenditures
for prescription drugs for the TennCare program.
o The TennCare Pharmacy Advisory Committee shall submit to the bureau of
TennCare both specific and general recommendations for drugs to be included on
any state PDL adopted by the bureau. In making its recommendations, the
committee shall consider factors including, but not limited to, efficacy, the use of
generic drugs and therapeutic equivalent drugs, and cost information related to each
drug. The committee shall also submit recommendations to the bureau regarding
computerized, voice, and written prior authorization, including prior authorization
criteria and step therapy.
o The state TennCare pharmacy advisory committee shall include evidence-based
research in making its recommendations for drugs to be included on the PDL.
o The TennCare bureau shall consider the recommendations of the state TennCare
pharmacy advisory committee in amending or revising any PDL adopted by the
bureau to apply to pharmacy expenditures within the TennCare program. The
recommendations of the committee are advisory only and the bureau may adopt or
amend a PDL regardless of whether it has received any recommendations from the
committee. It is the legislative intent that, insofar as practical, the TennCare bureau
shall have the benefit of the committee’s recommendations prior to implementing a
PDL or portions thereof.
Keep minutes of all meetings including votes on all recommendations regarding drugs to be
included on the state preferred drug list
The chair may request that other physicians, pharmacists, faculty members of institutions of
higher learning, or medical experts who participate in various subspecialties act as
consultants to the committee as needed.
Page 2 of 52
May 11, 2010 Tennessee PAC
PDL Decision Process
 The primary clinical decision that needs to be made is determining if the drugs within the
therapeutic class of interest can be considered therapeutic alternatives.
 A Therapeutic Alternative is defined by the AMA as: “drug products with different chemical
structures but which are of the same pharmacological and/or therapeutic class, and usually
can be expected to have similar therapeutic effects and adverse reaction profiles when
administered to patients in therapeutically equivalent doses”1.
 The Committee should not feel obligated to decide if every drug within the therapeutic class is
exactly equal to all other drugs within the class, nor should they feel obligated to decide if
every drug within the therapeutic class works equally well in every special patient population
or in every disease.
 In special situations (e.g., presence of comorbid conditions) and in special populations (e.g.,
pediatrics) use of a non-preferred drug might be the most appropriate therapy. These cases
can be handled through prior authorization (PA). PA serves as a “safety valve” in that it
facilitates use of the most appropriate agent regardless of PDL status.
Dependent upon diagnosis and length of therapy needed
LENGTH OF AUTHORIZATIONS:
to treat. (Most medications are used chronically, and thus would be approved for 1 year.)
1. Is there any reason the patient cannot be changed to a medication not requiring prior
approval within the same class?
Acceptable reasons include:
 Allergy to medications not requiring prior approval
 Contraindication to or drug-to-drug interaction with medications not requiring prior
approval
 History of unacceptable/toxic side effects to medications not requiring prior approval
2. The requested medication may be approved if both of the following are true:
 If there has been a therapeutic failure of at least two medications within the same
class not requiring prior approval (unless otherwise specified)
 The requested medication’s corresponding generic (if a generic is available and
preferred by the State) has been attempted and failed or is contraindicated
3. The requested medication may be approved if the following is true:
 An indication which is unique to a non-preferred agent and is supported by
peer-reviewed literature or an FDA approved indication exists.
-------------------------------------------------------------------------------------------------------------------------------The information provided for each drug class is organized into the following sections, when
applicable:
BACKGROUND:
 General overview
 Pharmacology
 Therapeutic effect(s)
 Adverse reactions
 Outcomes data
 Place in therapy according to current Treatment Guidelines
RECOMMENDATION:
 General recommendation regarding utility and therapeutic equivalence among the agents
in the class, as well as requirements for product availability (PDL placement)
1
AMA Policy H-125.991 Drug Formularies and Therapeutic Interchange
Page 3 of 52
May 11, 2010 Tennessee PAC
ANALGESIC AGENTS
RE-REVIEW: BUPRENORPHINE AND BUPRENORPHINE/NALOXONE
BACKGROUND
 Buprenorphine and buprenorphine/naloxone are treatment options for opiate dependent
patients.
 Buprenorphine exerts its physiological effects as a partial opioid agonist at the μ-opioid
receptor (associated with analgesia and dependence) and an antagonist at the κ-opioid
receptor (related to dysphoria). Naloxone acts as an antagonist at the μ-opioid receptor.
 During buprenorphine administration, opiate-dependent patients experience positive
subjective opioid effects but not the euphoric effects that may contribute to opiate abuse.
Buprenorphine and buprenorphine/naloxone are FDA indicated for the treatment of opioid
dependence.
 The most common adverse effects experienced with buprenorphine and naloxone
include: headache, nausea, pain, withdrawal syndrome, insomnia and sweating.
o No buprenorphine dosage adjustment required in renal dysfunction; however, a
hepatic dose adjustment is required.
o Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in
patients receiving buprenorphine. Respiratory depression, central nervous
system depression and impairment of mental or physical abilities have also been
reported with the use of buprenorphine
o Buprenorphine and buprenorphine/naloxone should be used with caution in
patients at higher risk of respiratory depression (ex. severe pulmonary function
impairment, myxedema or hypothyroidism, adrenal cortical insufficiency, central
nervous system depression or coma, toxic psychosis, prostatic hypertrophy or
urethral stricture, acute alcoholism, delirium tremens, kyphoscoliosis, biliary tract
dysfunction, acute abdominal conditions or patients considered debilitated).
o Buprenorphine can elevate cerebrospinal fluid pressure and should be used with
caution in patients with head injury
 Drug Abuse and Dependence
o Buprenorphine and buprenorphine/naloxone are controlled as schedule III
narcotics. Chronic administration of buprenorphine can produce dependence
characterized by withdrawal upon abrupt discontinuation or rapid taper.
o Buprenorphine/naloxone is highly likely to produce marked and intense
withdrawal symptoms if misused parenterally due to its naloxone component.
o Sublingually, buprenorphine/naloxone may cause opioid withdrawal symptoms in
patients if administered before the agonist effects of the opioid have subsided.
 According to the Drug Addiction Treatment Act of 2000 (DATA 2000), the ability to
prescribe buprenorphine or buprenorphine/naloxone for the maintenance or detoxification
of opioid dependence is limited to physicians who have obtained a waiver and a unique
Drug Enforcement Agency (DEA) number beginning with an X. The requirements for this
waiver include but are not limited to: specialization in addiction psychiatry, completion of
an eight hour certification program and the ability to refer addiction treatment patients for
appropriate counseling and other non-pharmacologic therapies.
 The United States Substance Abuse and Mental Services (SAMHSA) Clinical Guideline
for the Use of Buprenorphine in the Treatment of Opioid Addiction is the only detailed
guideline available at this time that provides specific treatment guidelines. SAMHSA
recommends the use of buprenorphine/naloxone for the induction, stabilization and
maintenance of opioid addiction treatment for most patients.
 Limited clinical trials have addressed brain μ-opioid receptor occupancy and smaller trials
have evaluated effects of different buprenorphine doses. The results have demonstrated
there is not a significant difference in receptor occupancy at higher buprenorphine doses
and no significant difference in subsequent effects at higher doses of 16mg and 32 mg.
o Greenwald et al conducted a randomized trial evaluating the occupancy of brain
μ-opioid receptors with different doses of buprenorphine. Primary endpoint was
to demonstrate in vivo buprenorphrine maintenance doses have a dose-
Page 4 of 52
May 11, 2010 Tennessee PAC
ANALGESIC AGENTS

dependent effect on μ-opioid receptors in the brain. Results demonstrated at low
doses (2mg) of buprenorphine μ-opioid receptor occupancy is approximately
41%, and then for 8, 16, and 32mg the occupancy increases to 83%, 92%, and
98%. Additionally, the study results also demonstrated that receptor availability
did not change significantly between between 16mg and 32mg but doses greater
than 32mg caused an increase the area under the curve (AUC) resulting in
longer duration of action.
o Correia et al evaluated escalating daily doses of buprenorphine/naloxone
(8mg/2mg vs 16mg/4mg vs 32mg/8mg) in adults with active opioid dependence.
Primary endpoints were opioid blockade and withdrawal effects. All three
buprenorphine doses provided incomplete blockade against opioid agonist
effects for 98 hours based on the number of subjective (drug effects) and
physiologic (blood pressure, heart rate, etc) effects measured. P values for most
measures were >0.05 with the exception of pupil diameter and oxygen saturation.
The 32 mg/8 mg dose produced less constricted pupils compared to the 8 mg/2
mg dose (P<0.05). The 8 mg/2 mg dose produced lower oxygen saturation as
compared to the 16 mg/4 mg dose (P<0.05). There were no significant
differences regarding symptoms of withdrawal among the study doses (P>0.05).
Authors concluded that doses greater than 8mg/2mg provided minimal increase
in blockade and withdrawal suppression.
o Bickel et al compared increasing maintenance dose ranges of 4mg to 8mg with
maintenance dose of 8mg to 16mg and 16mg to 32mg in adults with diagnosis of
opioid dependency. The primary endpoint was self reported measures (visual
analog scale and adjective rating scale) and observer measures. Results
demonstrated there were no statistically significant differences among the
different dosing schedules in any of the outcome measures, including subjective
opioid agonist and withdrawal effects (P values not reported). Additionally, with
the 32mg maintenance dose there were no significant increases observed in
opioid agonists effects compared to their usual maintenance dose (P values not
reported).
According to clinical trials and clinical guidelines from the Substance Abuse and Mental
Health Services Administration (SAMHSA) the expected maintenance dosing range and
recommended target dose is expected to be between 4-16mg/day with higher doses
ranging from 24-32mg for selected patients.
RECOMMENDATION
Buprenorphine and buprenorphine/naloxone are treatment options for opiate dependent
patients. As a partial μ-opioid agonist, buprenorphine has the advantages of providing the
positive subjective effects associated with opiate abuse and preventing withdrawal symptoms
while removing the euphoria associated with further opiate abuse. However, use of
buprenorphine hydrochloride for unsupervised administration should be limited to those
patients who cannot tolerate the buprenorphine hydrochloride/naloxone combination.
SAMHSA recommends the use of buprenorphine/naloxone for the induction, stabilization and
maintenance of opioid addiction treatment for most patients. The use of these agents is
limited to physicians who have obtained a waiver and a unique DEA number beginning with
an X. Use of these agents also requires intensive monitoring of patients during all phases of
treatment. Given the need for intensive monitoring of therapy, extensive training of
prescribers, and potential side effects of these products, it is recommended that
buprenorphine and buprenorphine/naloxone be available for the treatment of opioid
dependence but with clinical criteria and time limits to ensure their appropriate use.
COMMITTEE VOTE:
APPROVED
Page 5 of 52
DISAPPROVED
APPROVED with MODIFICATION
May 11, 2010 Tennessee PAC
ANALGESIC AGENTS
QUANTITY LIMITS
Subutex® 2 mg: 3 tabs/day
8 mg: 4 tabs/day 3 tabs/day
Suboxone® 2mg/0.5mg: 3 tabs/day
8mg/2mg: 4 tabs/day 3 tabs/day
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
QUANTITY LIMIT EXCEPTION CRITERIA
Approval for quantities greater than 24mg will be approved based on the following:
1. Member is being treated in initial induction phase.
2. Member is being treated for addiction with concomitant need for short term pain
management.
*Doses greater than 32mg will not be approved.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
CLINICAL CRITERIA
Subutex® will be approved for recipients who
Suboxone® will be approved for recipients who
meet ALL of the following criteria:
meet ALL of the following criteria:
-Diagnosis of opiate dependency
-Diagnosis of opiate dependency
-Physician must have completed certification
-Physician must have completed certification
program (DEA begins with “X”)
program (DEA begins with “X”)
-Physician has appropriately reviewed
-Physician has appropriately reviewed
Controlled Substances Database within the
Controlled Substances Database within the
past 30 days to ensure that concomitant
past 30 days to ensure that concomitant
narcotic use is not occurring
narcotic use is not occurring
-Must be unable to take Suboxone®
▪Patients who are pregnant
▪Allergy to naloxone
Subutex® and Suboxone® will not be approved for treatment of depression or pain
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2010.
Accessed April, 2010.
2. Thompson MICROMEDEX on-line © 1974-2010. Accessed April, 2010.
3. MedMetrics. Buprenorphine and buprenorphine/naloxone class review. 10/01/08.
4. Center for Substance Abuse Treatment. Clinical guidelines for the use of buprenorphine
in the treatment of opioid addiction. Rockville (MD): Substance Abuse and Mental
Health Services Administration (SAMHSA); DHHS Publication No. (SMA) 04-3939.
2004.
5. U.S. Department of Health and Human Services: Substance Abuse and Mental Health
Services. Drug addiction treatment act of 2000 [Guideline on the internet] Washington,
Page 6 of 52
May 11, 2010 Tennessee PAC
ANALGESIC AGENTS
6.
7.
8.
9.
D. C.: U.S. Department of Health and Human Services [cited 2010 April]:
http://buprenorphine.samhsa.gov/data.html.
Greenwald MK, Johanson C-E, Moody DE, et al. Effects of buprenorphine maintenance
dose on μ-opioid receptor availability, plasma concentrations, and antagonist blockage
in heroin-dependent volunteers. Neuropsychopharmacology. 2003;28:2000-2009.
Comer SD, Walker EA, Collins ED. Buprenorphine/naloxone reduces the reinforcing and
subjective effects of heroin in heroin-dependent volunteers. Psychopharmacology.
2005;181:664-675.
Correia CJ, Walsh SL, Bigelow GE, Strain EC. Effects associated with double-blind
omission of buprenorphine/naloxone over a 98-h period. Psychopharmacology. 2006
Dec;189(3):297-306.
Bickel WK, Amass L, Crean JP, Badger GJ. Buprenorphine dosing every 1,2, or 3 days
in opioid-dependant patients. Psychopharmacology. 1999 Sep;146(2):111-8.
Page 7 of 52
May 11, 2010 Tennessee PAC
ENDOCRINE & METABOLIC AGENTS
REVIEW: ORAL THROMBOPOIETIN RECEPTOR AGONIST
BACKGROUND
 Chronic idiopathic thrombocytopenia purpura (ITP) is an autoimmune bleeding disorder
characterized by continuous low platelets in the blood. The condition involves antibody
mediated platelet destruction and reduced platelet production. The signs and symptoms
of ITP can be variable ranging from no symptoms to severe bleeding.
 Current therapy options include corticosteroids, immunosuppressive agents,
immunoglobulins and splenectomy to help reduce platelet destruction. All of the treatment
options carry significant side effects and not all patients will respond to therapy.
Eltrombopag is an oral, non-peptide thrombopoietin (TPO) receptor agonist that acts to
stimulate the proliferation and differentiation of megakaryocytes, the bone marrow cells
that give rise to blood platelets. It is the first oral TPO receptor agonist approved for adult
patients with chronic ITP.
 Eltrombopag is FDA approved for the treatment of thrombocytopenia in adult patients
with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have had an
insufficient response to corticosteroids, immunoglobulins or splenectomy.
o Eltrombopag carries black box warning addressing significant hepatoxicity,
risk for bone marrow fibrosis, risk of worsening thrombocytopenia and
thromboembolic complications, and increased risk of cataracts.
o Eltrombopag should be used in patients with ITP whose degree of
thrombocytopenia and clinical condition increase the risk for bleeding.
o Eltrombopag is available through a restricted distribution program.
Prescribers, pharmacies, and patients must enroll in access program before
they can prescribe, dispense or receive eltrombopag.
 Limited placebo controlled clinical trials have been conducted to date.
 In a clinical study of 118 patients with chronic ITP, eltrombopag was compared to
9
placebo. Primary endpoint was platelet count of 50 x 10 /L on day 43. Twenty-eight
percent, 70%, and 81% of patients treated with eltrombopag 30 mg/day, 50 mg/day, or 75
mg/day, respectively, achieved platelet count response (defined as a shift from a baseline
platelet count of < 30 X 109/L to > 50 X 109/L at any time during the treatment period;
max treatment period of 6 weeks) vs. 11% of placebo-treated patients [p<0.001 for
eltrombopag 50 & 75 mg]. An increase in platelet counts to > 200 x 109/L occurred in
14%, 37%, and 50% of eltrombopag 30 mg/day, 50 mg/day, and 75 mg/day treated
patients vs. 4% of placebo-treated patients. There was 1 patient death reported
(eltrombopag-treated patient).
RECOMMENDATION
Chronic ITP involves antibody mediated platelet destruction and reduced platelet production.
Oral thrombopoietin (TPO) receptor agonists act to stimulate the proliferation and differentiation
of megakaryocytes that give rise to blood platelets. Oral TPO receptor antagonists are indicated
for the treatment of ITP when there is insufficient response to corticosteroids, immunoglobulins or
splenectomy. Clinical trials have demonstrated efficacy with eltrombopag compared to placebo.
Eltrombopag also carries black box warning addressing significant hepatoxicity, risk for bone
marrow fibrosis, risk of worsening thrombocytopenia and thromboembolic complications, and
increased risk of cataracts. Therefore it is recommended that eltrombopag be available for use
subject to clinical criteria to ensure appropriate use and minimize risk of adverse effects.
COMMITTEE VOTE:
APPROVED
Page 8 of 52
DISAPPROVED
APPROVED with MODIFICATION
May 11, 2010 Tennessee PAC
ENDOCRINE & METABOLIC AGENTS
PREFERRED
N/A
RE-REVIEW: ORAL THROMBOPOIETIN RECEPTOR AGONIST
NON-PREFERRED
Promacta® CC, QL (eltrombopag)
Clinical Criteria for Promacta®
Approval for Promacta® will be granted if ALL of the following criteria are met:
1. Diagnosis of idiopathic thrombocytopenia purpura (ITP)
2. Documentation of failure or insufficient response to adequate treatment with
corticosteroids AND immunoglobulins, OR splenectomy.
3. Documentation that patient’s thrombocytopenia and clinical condition puts the patient at
increased risk of bleeding.
4. Provider and patient are registered with Promacta® CaresTM program.
®
(Information regarding Promacta Cares
877-977-6622)
TM
program is available at: http://www.promactacares.com/index.html or by calling 1-
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
Quantity Limits for Promacta®
25mg 3 tab/day
50mg 1 tab/day
75mg 1 tab/day
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2010.
Accessed April, 2010.
2. Thompson MICROMEDEX on-line © 1974-2010. Accessed April, 2010.
3. RXCounselor: Promacta® by informedRX Drug Information Services. 04/06/2010.
4. Bussel JB, Cheng G, Saleh MN, Psaila B, Kovaleva L, Meddeb B, Kloczko J, Hassani
H, Mayer B, Stone NL, Arning M, Provan D, Jenkins JM. Eltrombopag for the treatment
of chronic idiopathic thrombocytopenic purpura. N Engl J Med. 2007 Nov
29;357(22):2237-47.
5. British Committee for Standards in Haematology General Haematology Task Force.
Guidelines for the investigation and management of idiopathic thrombocytopenic
purpura in adults, children and in pregnancy. Br J Haematol. 2003 Feb;120(4):574-96.
Available at: http://www.bcshguidelines.com/pdf/BJH574.pdf . Accessed 4/2010.
6. The American Society of Hematology ITP Practice Guideline Panel. Diagnosis and
treatment of idiopathic thrombocytopenia purpura: Recommendations of the American
Society of Hematology. Ann Intern Med. 1997;126: 319-326.
7. George JN, Woolf SH, Raskob GE. Idiopathic thrombocytopenic purpura: a guideline for
diagnosis and management of children and adults. American Society of Hematology.
Ann Med. 1998 Feb;30(1):38-44.
8. Promacta (eltrombopag) Prescribing Information. GlaxoSmithKline; Research Triangle
Park, NC: October 2008. Available at: http://www.promactacares.com/?a=promacta .
Accessed 4/2010.
Page 9 of 52
May 11, 2010 Tennessee PAC
DERMATOLOGIC AGENTS
RE-REVIEW: TOPICAL ANTIVIRALS
BACKGROUND
 The two most common cutaneous manifestations of the herpes simplex virus infection
are orolabial and genital herpes. Orolabial herpes, presents most commonly as cold
sores and is primarily herpes simplex (HSV)-1. Genital herpes is a common viral
sexually transmitted disease (STD) and is primarily HSV-2. Topical antivirals can reduce
the duration of viral shedding and the length of time before all lesions become crusted,
but this treatment is less effective than oral or intravenous therapies. Acyclovir and
penciclovir are the currently available prescription topical antivirals.
 Acyclovir and penciclovir are synthetic nucleoside analogs derived from guanine. The
agents are active against Herpes viridae including HSV-1 and HSV-2.
 Acyclovir cream is FDA indicated for the treatment of recurrent herpes labialis.
 Acyclovir ointment is FDA indicated for treatment of initial herpes genitalis and the
treatment of non-life threatening mucocutaneous herpes simplex infections in
immunocompromised patients.
 Penciclovir cream is FDA indicated for the treatment of recurrent herpes labialis.
 Adverse reactions most commonly associated with the topical antivirals are generally
localized to the application site and include transient burning and stinging, pruritis, and
dryness.
o
Topical antiviral agents should not be used in the eye or near the orbital area.
o
Topical antiviral agents should also not be used directly on mucus membranes
(inside mouth or nose).
o
Due to limited systemic absorption when acyclovir and penciclovir are
administered topically, no drug interactions are likely to occur and none are
documented with the topical antivirals.

Chen et al compared acyclovir 3% cream to penciclovir 1% cream in adult patients with
diagnosis of genital herpes, both treatments were initiated within 24 hours of onset of
symptoms and treatment duration was 7 days, N=205. Primary endpoints included time
to healing, resolution of all symptoms, absence of blisters, cessation of new blisters,
crusting, and loss of crust. Results demonstrated no statistically significant differences in
the primary endpoints. A decrease in crusting time was noted in patients with primary first
episodes of genital herpes with penciclovir compared to acyclovir (2.0 days vs 3.0 days;
P=0.03). A comparison of clinical efficacy in terms of cure rate at day 7 indicated that
there was no difference between penciclovir and acyclovir treatment (P=0.53).

Fermiano et al compared acyclovir 5% cream to penciclovir 1% cream in adult patients
who had history of frequent episodes of recurrent herpes labialis, N=40. The primary
endpoints were the clinicians’ judgment of the appearance of vesiculation to crusting and
patients’ experience of pain. In the acyclovir group, labial lesions reached a crusting
stage by 6 days, with pain ceasing at day 5 and in the penciclovir group, the crusting
phase was reached and pain ceased by day 4 (P= P=0.002).

Lin et al also compared acyclovir 5% cream to penciclovir 1% cream in adult patients with
diagnosis of herpes labialis, N=248. Primary endpoints were time to healing, resolution of
all symptoms, absence of blisters, cessation of new blisters, crusting and loss of crust.
Results demonstrated no statistically significant difference in time to achieve primary
endpoints. On day 7 evaluations, treatment was recorded as a clinical cure in 75.4% of
the penciclovir-treated patients and 64.9% of the acyclovir-treated patients. The
difference was not statistically significant (no P value reported).
Topical antivirals are commonly used to treat the symptoms of oral and genital herpes
infections. The agents have been shown to be efficacious when compared to placebo
and similar in efficacy when compared to each other. Additionally, no studies have been
conducted that directly compare oral and topical formulations for the treatment of oral or

Page 10 of 52
May 11, 2010 Tennessee PAC
DERMATOLOGIC AGENTS

genital herpes. Topical antivirals reduce the duration of viral shedding and the length of
time before all lesions become crusted, but this treatment is less effective than oral or
intravenous therapies. No antiviral agent currently available will eradicate HSV, and
treatment is aimed at managing rather than curing the disease.
There are currently no published guidelines specifically for the treatment of oral herpes.
The Centers for Disease Control (CDC) and the American College of Obstetricians and
Gynecologists (ACOG) both published specific guidelines for the treatment of genital
herpes. Clinical guidelines recommend the use of oral antiviral therapy for the
management of genital HSV infections. The guidelines do not recommend use of topical
antiviral agents, the guidelines state topical agents offer minimal clinical benefit and do
not add to the benefit of the oral medication.
RECOMMENDATION
Topical antivirals reduce the duration of viral shedding and the length of time before lesions
become crusted, however this treatment is less effective than oral or intravenous therapies. No
antiviral agent currently available will eradicate HSV; treatment is focused on managing rather
than curing the disease. Clinical trials have demonstrated the topical antivirals to be efficacious
when compared to placebo and similar in efficacy in head to head comparisons for the treatment
of oral and genital herpes and the agents can be considered therapeutic alternatives. No studies
have been conducted that directly compare oral and topical formulations for the treatment of oral
or genital herpes. Current clinical guidelines from the CDC and ACOG recommend the use of oral
antiviral agents and discourage the use of topical antiviral agents due to their limited clinical
benefit. However, the topical antiviral agents can provide symptomatic relief and possibly shorten
the duration of clinical symptoms; therefore it is recommended that at least one topical antiviral
agent be available for use.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
RE-REVIEW: TOPICAL ANTIVIRALS
PREFERRED
NON-PREFERRED
Zovirax® QL ointment (acyclovir)
Denavir® QL cream (penciclovir)
Zovirax® QL cream (acyclovir)
QUANITY LIMITS
Zovirax® ointment 1 tube/RX
Zovirax® cream 1 tube/RX
Denavir® cream 1 tube/RX
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2010.
Accessed March, 2010.
2. Thompson MICROMEDEX on-line © 1974-2010. Accessed March, 2010.
3. MedMetrics. Topical Antivirals class review. 11/06/2009.
4. Chen XS, Han GZ, Guo ZP, et al. A comparison of topical application of penciclovir 1%
cream with acyclovir 3% cream for treatment of genital herpes: a randomized, doubleblind, multicenter trial. Int J STD AIDS. 2000;11:568-73.
5. Femiano F, Gombos F, Scully C, et Al. Recurrent Herpes Labialis: efficacy of topical
therapy with penciclovir compared with acyclovir (aciclovir). Oral Dis. 2001;7:31-3.
Page 11 of 52
May 11, 2010 Tennessee PAC
DERMATOLOGIC AGENTS
6. Lin L, Chen XS, Cui PG, et al. Topical application of penciclovir cream for the treatment
of herpes simplex facialis/labialis: a randomized, double blind, multicenter, acyclovircontrolled trial. J Dermatolog Treat. 2002;13:67-72.
7. Centers for Disease Control and Prevention. Sexually Transmitted Diseases Treatment
Guidelines, 2006. MMWR 2006;55(No. RR-11):1-100 [cited 2009 September 2].
Available at: http://www.cdc.gov/std/treatment/.
8. American College of Obstetricians and Gynecologists. ACOG practice bulletin: clinical
management guidelines for obstetrician-gynecologists. Gynecologic herpes simplex
virus infections. Obstet Gynecol. 2004;104(5):1111-7.
Page 12 of 52
May 11, 2010 Tennessee PAC
DERMATOLOGIC AGENTS
RE-REVIEW: TOPICAL AGENTS FOR BURNS
BACKGROUND
 Burns predispose patients to infection due to a loss of the protective barrier function of
the skin, which leads to possible entry of microorganisms and can cause systemic
immunosuppression. Complications secondary to infections are the major cause of
morbidity and mortality in patients with severe burns. Closure and healing of the wound
are the major goals of burn wound management. Topical agents for burns are utilized for
decreasing the bacterial burden of burn wounds thus minimizing the incidence of
infection. Currently available agents include mafenide acetate and silver sulfadiazine.
 Both agents exert bactericidal activity against gram negative and gram positive bacteria
associated with skin infections.
 FDA-Approved Indications
Indication
Adjunct therapy in the treatment
of second- and third-degree burns
Adjunct therapy in the prevention of
burn wound infections

Mafenide Acetate

Cream only

Solution only
Silver sulfadiazine


The most common adverse effects seen with the topical agents for burns are associated
with the application site and include transient pain and burning sensation, rash, and skin
irritation. More severe adverse effects seen with mafenide therapy include blisters,
erythema, and swelling.
o
Silver sulfadiazine is contraindicated in pregnant women approaching or at term,
premature infants, and infants less than two months old.
o
There is a potential for cross-sensitivity with sulfonamides in patients with an
allergy to silver sulfadiazine.
o
Silver sulfadiazine also has the potential to cause hemolysis in patients with
glucose-6-phosphate dehydrogenase-deficiency.
o
Silver sulfadiazine has the potential to inactivate topical proteolytic enzymes
when used concurrently on wound area.
o
Superinfections, including fungal proliferation may occur with use of silver
sulfadiazine.
o
Caution should be used in patients with glucose-6-phosphate dehydrogenase
deficiency and use of mafenide acetate due to risk of fatal hemolytic anemia with
disseminated intravascular coagulation.
o
Mafenide acetate inhibits carbonic anhydrase which can cause metabolic
acidosis. Patients with extensive second-degree or partial thickness burns and
those with pulmonary or renal dysfunction should be monitored closely for acidbase disturbances.
There are no significant drug-drug interactions identified with the topical agents
for burns.
Few clinical trials evaluating the efficacy and safety of the topical agents for burns were
identified and no head to head comparisons are available. Additionally, no evidenced
based clinical guidelines have been published addressing standard of care for minor to
moderate burns.
A recent Cochrane review, evaluated the available literature regarding topical silver
preparations for preventing would infections. The authors concluded there is insufficient
data to give evidence based recommendations on the use of silver preparations.
Although limited clinical literature is available, the topical agents for burns are widely
used in burn care. Standard therapy for burn victims includes excision of burned tissue,
debridement of necrotic tissue, as well as grafting of skin or skin substitutes. Topical antio



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May 11, 2010 Tennessee PAC
DERMATOLOGIC AGENTS
infective agents are utilized for decreasing the bacterial burden of burn wounds, thus
minimizing the incidence of infection. Areas affected by burns often do not have
adequate blood supply to provide necessary effects from systemic antibiotics, the topical
agents for burns allow for preventing bacterial contamination without requiring systemic
blood vessels.
RECOMMENDATION
Complications secondary to infections are the major cause of morbidity and mortality in patients
with moderate to severe burns. Topical agents for burns are utilized for decreasing the bacterial
burden of burn wounds and minimizing the incidence of infection. There are currently no evidence
based clinical guidelines available and limited clinical trials evaluating efficacy of the topical agents
for burns. However, given that the agents are broadly active against many bacteria and some
fungi, and are an established part of burn and wound care, it is recommended that at least one
topical agent for burn treatment is available for use.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
RE-REVIEW: TOPICAL AGENTS FOR BURNS
PREFERRED
NON-PREFERRED
silver sulfadiazine (compares to Silvadene®)
Silvadene® (silver sulfadiazine)
Thermazene® (silver sulfadiazine)
Sulfamylon® (mafenide acetate)
®
SSD (silver sulfadiazine)
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2010.
Accessed March 2010.
2. Thompson MICROMEDEX on-line © 1974-2010. Accessed March 2010.
3. MedMetrics. Topical agents for burns class review. 10/08/2009.
4. Madoff Lawrence C, Pereyra Florencia. Chapter e15. Infectious Complications of Burns
and Bites (Chapter). Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL,
Jameson JL, Loscalzo J: Harrison's Principles of Internal Medicine. 17th ed. 2008
Available from: http://www.accessmedicine.com/content.aspx?aID=2885387.
5. Mozingo DW, Cioffi WG, Pruitt BA. Burns. In: Bongard FS, Sue DY, eds. Current Critical
Care Diagnosis & Treatment. 2nd ed. New York: McGraw-Hill; 2003.
6. Neely AN, Gardner J, Durkee P, et al. Are Topical Antimicrobials Effective Against
Bacteria that are Highly Resistant to Systemic Antibiotics. J Burn Care Res 2009;30:1929.
7. Storm-Versloot MN, Vos CG, Ubbink DT, et al. Topical Silver for preventing wound
infection. Cochrane Database Syst Rev. 2010 March 17; 3: CD006478.
Page 14 of 52
May 11, 2010 Tennessee PAC
DERMATOLOGIC AGENTS
RE-REVIEW: TOPICAL ANTIBIOTIC AGENTS FOR SKIN AND SOFT TISSUE INFECTIONS
BACKGROUND
 Infections of the skin and soft tissues are common infections seen in both community and
hospital settings. Humans are natural hosts for many microorganisms that colonize the
skin as normal flora. Staphylococcus aureus and Streptococcus pyogenes are infrequent
resident flora, but they account for a wide variety of bacterial infections. The topical
antibacterial agents for skin and soft tissue infections are approved for the treatment
and/or prevention of various superficial skin infections and impetigo. The agents included
in this review are topical gentamicin, mupirocin, and retapamulin.
 All of the topical agents exert their pharmacological effect by inhibiting bacterial protein
synthesis. Retapamulin has a unique binding interaction when affecting bacterial protein
synthesis which allows it to be a therapy option when there is identified resistance to
mupirocin.
 FDA-Approved Indications:
Indication
Gentamicin
Treatment of primary and
secondary skin infections
Treatment of secondarily infected
traumatic skin lesions due to
susceptible
strains of Staphylococcus aureus
and Streptococcus pyogenes
Topical treatment of impetigo due to
S Aureus and S Pyogenes
Eradication of nasal colonization
with
MRSA in adult patients and
health care workers
Adults and pediatric patients ≥9
months for the topical treatment of
impetigo due to S aureus
(methicillin-susceptible isolates only)
or S pyogenes.
Treatment of corticosteroidresponsive dermatoses with
secondary infection

Mupirocin
Retapamulin
Neomycin,
polymyxin
B, and
hydrocortisone
Bacitracin,
neomycin,
polymyxin
B, and
hydrocortisone


(cream)

(ointment)

(nasal)



The most common adverse reactions seen with topical antibiotic agents affect the
application site and include erythema, dry skin, pruritis, and transient burning/stinging.
o
Caution should be used if skin irritation is present at infected site.
o
Prolonged utilization of topical antibiotic agents can increase risk of restistance
and predispose patient to secondary infections.
Mupirocin nasal ointment should not be used concurrently with any other nasal
products.
o Due to limited systemic absorption when the topical antibacterial agents are
administered, no drug interactions are likely to occur and none are documented
with these agents.
Clinical trials comparing the use of topical antibiotic agents for treatment or eradication
are limited and clinical trials addressing use of mupirocin for prevention in relation to S.
aureus infections and risk of noscomial S. aureus infections have produced inconsistent
results. Head to head comparisons of the agents are also limited.
o

Page 15 of 52
May 11, 2010 Tennessee PAC
DERMATOLOGIC AGENTS



Additionally, mupirocin nasal ointment has been shown to achieve greater nasal carriage
eradication rates compared to placebo; however, duration of hospitalization, in-hospital
mortality, and time to nosocomial S aureus infection have not been found to be
statistically significantly different with mupirocin.
There are limited published clinical trials evaluating the safety and effectiveness of
retapamulin ointment. Compared to placebo, retapamulin ointment has been associated
with a better clinical response. No published studies comparing retapamulin to mupirocin
for the treatment of impetigo are available at this time. Manufacturer recommends to
prevent bacterial resistance, retapamulin use should be reserved for treatment of
susceptible bacteria.
Topical antibiotic agents are commonly used to treat skin infections such as impetigo and
other S. aureus related skin infections. Current clinical guidelines from the Infectious
Disease Society of America’s (IDSA) Practice Guidelines for Skin and Soft Tissue
infections and the American Academy of Family Physicians’ (AAFP) treatment guidelines
for Impetigo recommend topical mupirocin as first line therapy for treatment of impetigo.
Additionally, the International Society for Peritoneal Dialysis (ISPD) guidelines also
recommend topical mupirocin at catheter exit site for prevention of catheter infections.
Mupirocin ointment should be avoided in patients with polyurethane catheters and
mupirocin cream should be substituted. The guidelines were published prior to the
approval of retapamulin.
RECOMMENDATION
The topical antibacterial agents for skin and soft tissue infections are approved for the treatment
and/or prevention of various superficial skin infections and impetigo. Clinical trials have
demonstrated efficacy for the treatment and eradication of various organisms but have not yet
demonstrated a clear role of the agents in the prevention of infections. Current clinical guidelines
from IDSA, AAFP, all recommend topical mupirocin as first line treatment for impetigo and the
ISPD guidelines recommend mupirocin for prevention of catheter site infections. Therefore it is
recommended that at least one mupirocin agent be available for use.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
RE-REVIEW: TOPICAL ANTIBIOTIC AGENTS FOR SKIN AND SOFT TISSUE INFECTIONS
PREFERRED
NON-PREFERRED
gentamicin
mupirocin ointment
Altabax® (retapamulin)
®
Bactroban (mupirocin)
®
Centany (mupirocin)
®
Cortisporin cream (neomycin, polymyxin B, and hydrocortisone)
Cortisporin® ointment (bacitracin, neomycin, polymyxin B, and
hydrocortisone)
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2010.
Accessed April, 2010.
2. Thompson MICROMEDEX on-line © 1974-2010. Accessed April, 2010.
3. MedMetrics. Topical Antibiotic agents for MRSA class review. 10/13/2010.
4. Perl TM, Cullen JJ, Wenzel RP, et al. Intranasal mupirocin to prevent postoperative
Staphylococcus aureus infections. N Engl J Med 2002; 346(24):1871-7.
5. Mody L, Kauffman CA, McNeil SA, et al. Mupirocin-based decolonization of
Staphylococcus aureus carriers in residents of 2 long-term care facilities: a randomized,
double-blind, placebo-controlled trial. Clin Infect Dis. 2003;37:1467-74.
6. Wertheim HFL, Vos M, Ott A, et al. Mupirocin prophylaxis against Staphylococcus
aureus infections in nonsurgical patients. Ann Intern Med 2003; 140:419-25.
7. Koning S, van der Wouden JC, Chosidow O, Twynholm M, Singh KP, Scangarella N et
Page 16 of 52
May 11, 2010 Tennessee PAC
DERMATOLOGIC AGENTS
al. Efficacy and safety of retapamulin ointment as treatment of impetigo: randomized
double-blind multicenter placebo controlled trial. British Journal of Dermatology.
2008;158:1077-82
8. Stevens DL, Bisno AL, Chambers HF, Everett ED, Dellinger P, Goldstein EJ, Gorbach
SL, Hirschmann JV, Kaplan EL, Montoya JG, Wade JC; Infectious Diseases Society of
America. Practice guidelines for the diagnosis and management of skin and soft-tissue
infections. Clin Infect Dis. 2005;41:1373-406.
9. Cole C, Gazewood J. Diagnosis and treatment of impetigo. Am Fam Physician. 2007
Mar 15;75(6):859-64.
10. International Society for Peritoneal Dialysis (ISPD). Peritoneal dialysis-related
infections: recommendations: 2005 update. Peritoneal Dialysis International
2005;25:107–31.
Page 17 of 52
May 11, 2010 Tennessee PAC
DERMATOLOGIC AGENTS
RE-REVIEW: SCABICIDES AND PEDICULICIDES
BACKGROUND
 Scabies and pediculosis are caused by external parasites. Scabies is caused by a
parasitic mite. Pediculi or lice are obligate human parasites, causing infestations on the
head, body, and pubic regions. While the skin conditions are associated with low
morbidity, they are common causes of skin rash, pruritus, and secondary skin infections,
and are contagious. Topical scabicides and pediculicides are the primary form of
treatment for these conditions. This review will focus on currently available prescription
agents including benzyl alcohol, crotamiton, lindane, malathion, and permethrin.
 The topical scabicides and pediculicides have varying mechanisms of action. The ideal
therapy for eradication of the organisms is a combination of pediculicidal and complete
ovicidal activity.
o Benzyl alcohol exerts its pharmacological effect by inhibiting lice respiration and
subsequently causing asphyxiation.
o Crotamiton’s mechanism of action is unknown however it is considered
scabicidal in its effect against Sarcoptes scabiei.
o Lindane is absorbed directly into the exoskeleton of the parasite; it exerts its
pharmacological effect by stimulating the CNS system of the parasite causing
seizures and death.
o Malathion is an organophosphate that acts to inhibit acetylcholinesterase leading
to rapid pediculicidal and ovicidal activity, selective for the parasite. In humans,
topical malathion is rapidly detoxified and excreted (less than 10% is absorbed
through skin).
o Permethrin acts to inhibit sodium channels and sodium movement across nerve
cell membranes resulting in paralysis and death in the parasite.
 FDA approved indications & applicable age ranges:
Drugs
Benzyl Alcohol
(can be used for anyone > 6 months of age)
Crotamiton
(Safety/efficacy not established in pediatrics)
Lindane
(Not recommended in infants/individuals <50 kg)
Malathion
(Safety/efficacy not established <6 years)
Permethrin
(Safety/efficacy not established <2 months of age)

Scabies
Head Lice
Head & Pubic
Lice







The most common adverse reactions with all of the topical scabicides and pediculicides
are primarily localized to the application site and include pruritis, transient burning,
stinging, and mild skin irritation. More severe effects associated specifically with lindane
therapy include ataxia, nausea, vomiting, and seizures.
Page 18 of 52
o
Lindane carries a black box warning addressing its use should be restricted as
second line therapy, a warning related to increased risk of neurotoxicity, a
warning that its use is contraindicated in infants and individuals with seizure
disorders, and lastly a warning emphasizing counseling on proper application of
therapy.
o
The FDA issued a Public Health Advisory reiterating the four parts of the black
box warning for the general public.
o
Lindane is contraindicated in patients with known seizure disorders.
o
Lindane is contraindicated in neonates and infants due to possible increased skin
absorption and not sufficiently developed liver enzyme system.
May 11, 2010 Tennessee PAC
DERMATOLOGIC AGENTS
o
Lindane is contraindicated in patients with concurrent crusted (Norwegian)
scabies or other skin conditions (atopic dermatitis and psoriasis) that may
increase absorption.
o
Malathion is contraindicated in neonates and infants due to possible increased
skin absorption.
o
Caution should be used with malathion not to expose lotion/hair to electric heat
sources, lotion is flammable
o
Caution should be used with lindane and use of other creams, oils, or ointments;
concomitant use can increase absorption of lindane.
o
Caution should be used with lindane and concomitant use of other medications
that could lower the seizure threshold and cause increased risk of seizure
activity.
o
Extreme caution should be used when applying lindane to individuals weighing
less than 50 kg due to higher surface to volume ratio and potential for increased
systemic absorption, generally use in this population is not recommended.
o
Caution should be used with all topical scabicides and pediculicides to ensure
these agents are for external use only; avoid contact with eyes.
o
Intravenous administration of benzyl alcohol has been associated with neonatal
gasping syndrome; patients’ less than 1 month old receiving topical benzyl
alcohol could be at increased risk for gasping syndrome.
There are no identified significant drug-drug interactions with the topical
scabicides and pediculicides.
Clinical trials have demonstrated efficacy of permethrin, crotamiton, lindane, and
malathion for the treatment of scabies and lice.
o Schultz et al compared lindane lotion to permethrin cream in patients diagnosed
with scabies (N=467). Primary endpoint was efficacy and secondary endpoints
were side effects. Ninety one percent and 86% patients treated with permethrin
and lindane, respectively had complete resolution after treatment (P=0.18 and
P=0.30). The most frequent adverse effects were transient burning or stinging
and new or increased pruritis; Events were more frequent following permethrin
treatment and appeared to be related to the severity of the infestation.
o Taplin et al compared the use of permethrin cream to crotamiton cream in the
treatment of scabies for 1 month in children 2 months to 5 years of age (N=47).
Primary endpoint was efficacy. Fourteen of 47 (30%) children were considered
cured two weeks after permethrin treatment compared to only 6 of 47 (13%)
subjects treated with crotamiton. Four weeks after treatment 89% of patients
treated with permethrin and 60% of patients treated with crotamiton were
considered cured. These results found permethrin to be significantly better then
crotamiton (P=0.002).
o Bowerman et al compared lindane shampoo to permethrin cream rinse in
patients with diagnosis of head lice (N=1040). Primary endpoint was efficacy
(cure rate) and secondary endpoint was adverse effects. Ninety eight percent of
patients treated with permethrin and 76% treated with lindane were louse-free 2
weeks after treatment (P<0.001). Mild dermal reactions, such as pruritus or
erythema, occurred in 1.2% of permethrin-treated patients and 2.6% of lindanetreated patients.
The FDA approval of topical benzyl alcohol was based on the results of two multicenter,
randomized, double-blind, placebo/vehicle-controlled studies in 628 patients (≥6 months)
with active head lice infestation. These trials found a greater clearance of lice 14 days
after final treatment with benzyl alcohol compared to placebo. The studies have not been
published yet in peer-reviewed journals.
o


Page 19 of 52
May 11, 2010 Tennessee PAC
DERMATOLOGIC AGENTS

Lice and scabies infections can be difficult to control. Common reasons for treatment
failures include misdiagnosis, noncompliance, failure to follow instructions correctly, not
enough pediculicide applied, and re-infestation. Additionally, resistance to certain
scabicides and pediculicides can also develop and has been documented in many
geographical regions, has been documented specifically with permethrin and malathion.
The FDA issued a public advisory recommending lindane be reserved for second line
therapy after treatment failure with first line agents due to its significant side effect profile.
Current clinical guidelines from the American Academy of Pediatrics (AAP) and the
Centers for Disease Control (CDC) recommend permethrin as first line therapy for the
treatment of lice and scabies due to its efficacy, safety profile, and wide availability. The
guidelines recognize malathion as an alternative therapy to permethrin and recommend
reserving lindane for individuals who have experienced treatment failure on first line
agents. Benzyl alcohol is the newest agent approved for treatment of lice, it is not yet
included in any of the current guidelines; however it is indicated for treatment in younger
children due to its less toxic side effect profile when compared to traditional pediculicide
agents. Benzyl alcohol does not have risk of developing resistance based on its unique
mechanism of action compared other traditional therapies.
RECOMMENDATION
Scabies and lice are contagious parasitic infections associated with low morbidity but can become
causes of skin rash, pruritus, and secondary skin infections. Topical scabicides and pediculicides
are the primary form of treatment for these conditions. Clinical trials have demonstrated efficacy of
these agents. Topical benzyl alcohol has limited clinical trial data, but has less toxic side effect
profile when compared to traditional pediculicide agents. The FDA issued a public advisory
recommending lindane be reserved for second line therapy after treatment failure with first line
agents due to its significant neurotoxic side effect profile; therefore, it can be considered an inferior
agent. Current clinical guidelines from the AAP and the CDC recommend permethrin as first line
therapy for the treatment of lice and scabies due to its efficacy and safety profile. The guidelines
recognize malathion as an alternative therapy to permethrin. Therefore it is recommended at least
two scabicide/pediculicide agents be available for use; one of which should be permethrin.
Additionally, it is recommended that lindane be subject to clinical criteria due to its neurotoxic side
effect profile and to reserve its use as second line therapy.
PREFERRED
Acticin® (permethrin)
Ovide® (malathion)
Permethrin
RE-REVIEW: SCABICIDES AND PEDICULICIDES
NON-PREFERRED
Elimite® (permethrin)
Eurax® (crotamiton)
lindaneCC
malathion
Ulesfia® QL (benzyl alcohol)
Clinical Criteria for Lindane
–Not approved for premature infants or individuals with uncontrolled seizure disorders
–Patients must have tried and failed, or be unable to tolerate, all other approved therapies as
listed below:
o For use in lice infestation: permethrin, malathion, and benzyl alcohol
o For use in scabies: permethrin and crotamiton
COMMITTEE VOTE:
APPROVED
Page 20 of 52
DISAPPROVED
APPROVED with MODIFICATION
May 11, 2010 Tennessee PAC
DERMATOLOGIC AGENTS
Quantity Limit for Ulesfia®
2 bottles per RX
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2010.
Accessed March, 2010.
2. Thompson MICROMEDEX on-line © 1974-2010. Accessed March, 2010.
3. MedMetrics. Scabicides and Pediculicides class review. 11/16/2009.
4. Lebwohl M, Clark L, Levitt J. Therapy for Head Lice Based on Life Cycle, Resistance, and
Safety Considerations. Pediatrics. 2007; 119:965-974.
5. Food and Drug Administration. FDA Public Health Advisory: Safety of Topical Lindane
Products for the Treatment of Scabies and Lice. [cited 2010 Mar 30] Available at:
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandPr
oviders/ucm110845.htm.
6. Schultz MW, Gomez M, Hansen RC, et al. Comparative study of 5% permethrin cream
and 1% lindane lotion for the treatment of scabies. Arch Dermatol. 1990;126:167-70.
7. Treatment of Head Lice. Centers for Disease Control and Prevention. 2008. [cited 2009
June 29] Available at: http://www.cdc.gov/lice/head/treatment.html.
8. Centers for Disease Control and Prevention. Ectoparasitic infections. In: Centers for
Disease Control and Prevention. Sexually Transmitted Diseases Treatment Guidelines,
2006. MMWR 2006;55 (No. RR-11):1-100. [cited 2006 Oct 27] Available at:
http://www.cdc.gov/std/treatment/2006/ectoparasitic.htm.
9. Frankowski B, Weiner L. Head lice. Pediatrics 2002:110(3);638-643. [cited 2009 Nov 3]
Available at: http://aappolicy.aappublications.org/cgi/content/full/pediatrics;110/3/638.
10. American Academy of Pediatrics. Pediculosis Capitis (Head Lice). In: Pickering LK, ed.
Red Book: 2009 Report of the Committee on Infectious Diseases. 28th ed. Elk Grove
Village, IL: American Academy of Pediatrics; 2009:495-497. Available at:
http://aapredbook.aappublications.org/cgi/content/full/2009/1/3.94. Accessed March 29,
2010.
11. American Academy of Pediatrics. Pediculosis Corporis (Body Lice). In: Pickering LK, ed.
Red Book: 2009 Report of the Committee on Infectious Diseases. 28th ed. Elk Grove
Village, IL: American Academy of Pediatrics; 2009:498. Available at:
http://aapredbook.aappublications.org/cgi/content/full/2009/1/3.95. Accessed March 29,
2010.
12. American Academy of Pediatrics. Pediculosis Pubis (Pubic Lice, Crab Lice). In: Pickering
LK, ed. Red Book: 2009 Report of the Committee on Infectious Diseases. 28th ed. Elk
Grove Village, IL: American Academy of Pediatrics; 2009:499. Available at:
http://aapredbook.aappublications.org/cgi/content/full/2009/1/3.96. Accessed April 1,
2010.
13. American Academy of Pediatrics. Drugs for Parasitic Infections. In: Pickering LK, ed. Red
Book: 2009 Report of the Committee on Infectious Diseases. 28th ed. Elk Grove Village,
IL: American Academy of Pediatrics; 2009:783-816. Available at:
http://aapredbook.aappublications.org/cgi/content/full/2009/1/4.10. Accessed March 29,
2010.
Page 21 of 52
May 11, 2010 Tennessee PAC
GASTROINTESTINAL AGENTS
RE-REVIEW: ANTIEMETICS, DELTA-9-THC DERIVATIVES
BACKGROUND






In the treatment of cancer, nausea and vomiting can be significant problems. Physiologic
pathways involved in the treatment of nausea and vomiting primarily involve dopamine
and serotonin (5-HT). Other receptors which have a lesser role include muscarinic,
opiate, histamine H1, cannabinoid, and neurokinin 1 (NK1). This review will focus on the
available delta-9-tetrahydrocannabinol (THC) derivative antiemetics, dronabinol and
nabilone.
Although the exact mechanism of action is unknown, cannabinoid receptors in neural
tissues may play a role in mediating the antiemetic effects of dronabinol, nabilone and
other cannabinoids.
Dronabinol and nabilone are FDA approved for the treatment of chemotherapy-induced
nausea and vomiting (CINV) in patients who have failed to respond to conventional
antiemetic treatments. Dronabinol is also FDA approved for the management of anorexia
associated with weight loss in patients with acquired immune deficiency syndrome
(AIDS).
The most commonly encountered adverse reactions were ataxia, concentration
difficulties, dry mouth, drowsiness, euphoria, headache, and vertigo. A cannabinoid doserelated “high” has been reported by dronabinol patients receiving the antiemetic dose
(24%) as well as the lower appetite stimulant dose (8%) in clinical trials. Euphoria has
been reported in up to 38% of patients receiving nabilone.
o Dronabinol is the principal psychoactive substance present in Cannabis sativa L
(marijuana) and nabilone is a synethetic cannabinoid which is pharmacologically
similar to marijuana. Nabilone (Schedule CII) and dronabinol (Schedule CIII) are
regulated under the Controlled Substances Act and should be used with caution
in patients with a history of substance abuse.
o Caution is advised for patients with cardiac, psychiatric, or seizure disorders.
Additionally, nabilone should be used with caution in patients with mania,
depression or schizophrenia as symptoms of these disease states may be
unmasked by use.
o Dronabinol and nabilone should be used with caution in patients receiving
concomitant therapy with sedatives, hypnotics, or other psychoactive substances
due to the potential for additive or synergistic central nervous system effects.
There are no published clinical trials comparing dronabinol to nabilone for CINV. For the
management of CINV, meta-analyses and head-to-head trials have shown that the
cannabinoids were more effective than placebo and some trials reported that they were
more effective than prochlorperazine and metoclopramide.
o Tramer, et al conducted a meta-analysis of randomized, controlled trails
published between 1975 and 1997 comparing cannabinoids to conventional
antiemetics for the treatment of CINV. Cannabinoids were more effective
antiemetics for complete control of nausea (RR, 1.38; 95% CI, 1.18 to 1.62; NNT,
6) and for complete control of vomiting (RR, 1.28; 95% CI, 1.08 to 1.51; NNT, 8).
Side effects that were considered harmful that were reported more often with
cannabinoids were dizziness, dysphoria, depression, hallucinations, paranoia
and arterial hypotension.
Studies evaluating the efficacy of dronabinol for stimulating appetite and promoting
weight gain in patients with AIDS have reported modest results with megestrol shown to
be more effective.
o Timone, et al conducted a randomized controlled trial comparing dronabinol (D)
versus megesterol (M750) versus combination therapy (M750 +D, M250 +D) in
patients with HIV wasting syndrome. The mean weight change+SE over 12
weeks was as follows: D, –2.0+1.3 kg; M750, +6.5+1.1 kg; M750+D, +6.0+1.0
kg; and M250+D, –0.3+1.0 kg (the difference among treatment arms; P=0.0001).
Page 22 of 52
May 11, 2010 Tennessee PAC
GASTROINTESTINAL AGENTS

Guidelines from the American Society of Clinical Oncology and the National
Comprehensive Cancer Network both recommend the use of aprepitant, along with a 5HT3 receptor antagonist plus dexamethasone, as first-line therapy for the prevention of
nausea and vomiting induced by moderately and highly emetogenic chemotherapy
agents. The cannabinoids are reserved for patients who are intolerant or refractory to
first-line agents.
RECOMMENDATION
Dronabinol and nabilone are FDA approved for the treatment of CINV in patients who have failed
to respond to conventional antiemetic treatments. National and international consensus guidelines
recommend the use of aprepitant, along with a 5-HT3 receptor antagonist plus dexamethasone, as
first-line therapy for the prevention of nausea and vomiting induced by moderately and highly
emetogenic chemotherapy agents. Clinical guidelines reserve the use of cannabinoids for CINV
for patients who are intolerant or refractory to first-line agents. Additionally, dronabinol is FDA
approved for the management of anorexia associated with weight loss in patients with AIDS;
however, megestrol has been shown to be more effective. There are no head-to-head studies that
have compared dronabinol to nabilone for their FDA-approved indications and these agents can
be considered therapeutic alternatives. Dronabinol and nabilone both have a high abuse potential,
are regulated under the Controlled Substances Act and are not considered first line therapy for
their approved indications. Therefore, it is recommended that all agents in this class should be
subject to clinical criteria to reserve their use for patients who are intolerant or refractory to firstline agents.
COMMITTEE VOTE:
APPROVED
PREFERRED
N/A
DISAPPROVED
APPROVED with MODIFICATION
RE-REVIEW: ANTIEMETICS, DELTA-9-THC DERIVATIVES
NON-PREFERRED
Cesamet® CC (nabilone)
dronabinolCC (compares to Marinol®)
Marinol® CC (dronabinol)
Clinical Criteria for dronabinol

For treatment of severe chemotherapy induced nausea and vomiting, associated with
cancer chemotherapy, ALL of the following criteria must be met:
1) Recipient must have tried and failed, or have intolerance or contraindication to, or have a
medical reason they cannot take at least one the following anti-nauseants :
• Anticholinergic agents (i.e. promethazine, prochlorperazine)
• Associated corticosteroids (i.e. dexamethasone)
• Pro-kinetic agents (i.e. metoclopramide)
2) Recipient must have tried and failed, or have intolerance or contraindication to, or have a
medical reason that they cannot take a preferred 5-HT3 receptor antagonist
3) Recipient must have failure, intolerance, medical reason, or contraindication that prohibits
taking Emend + 5HT3 receptor antagonist + corticosteroid.

For the treatment of AIDS-related wasting, recipeint must have tried and failed, or have
intolerance or contraindication to, or have a medical reason they cannot take megestrol
acetate oral suspension (Megace®).
COMMITTEE VOTE:
APPROVED
Page 23 of 52
DISAPPROVED
APPROVED with MODIFICATION
May 11, 2010 Tennessee PAC
GASTROINTESTINAL AGENTS
Clinical Criteria for Cesamet®
For treatment of severe chemotherapy induced nausea and vomiting, associated with cancer
chemotherapy, ALL of the following criteria must be met:
1) Recipient must have tried and failed, or have intolerance or contraindication to, or have a
medical reason they cannot take at least one the following anti-nauseants :
• Anticholinergic agents (i.e. promethazine, prochlorperazine)
• Associated corticosteroids (i.e. dexamethasone)
• Pro-kinetic agents (i.e. metoclopramide)
2) Recipient must have tried and failed, or have intolerance or contraindication to, or have a
medical reason that they cannot take a preferred 5-HT3 receptor antagonist
3) Recipient must have failure, intolerance, medical reason, or contraindication that prohibits
taking Emend + 5HT3 receptor antagonist + corticosteroid.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2010.
Accessed April, 2010.
2. Thompson MICROMEDEX on-line © 1974-2010. Accessed April, 2010.
3. Med Metrics. Antiemetics, Delta-9-Tetrahydrocannabinol Derivatives Therapeutic Class
Review. January 15, 2010.
4. American Society of Clinical Oncology; Kris MG, Hesketh PJ, Somerfield MR, et al.
American Society of Clinical Oncology guideline for antiemetics in oncology: update
2006. J Clin Oncol. 2006;24(18):2932-47.
5. National Comprehensive Cancer Network. NCCN Clinical practice guidelines in
oncology: Antiemesis v.4.2009 [monograph on the internet]. Jenkintown (PA): National
Comprehensive Cancer Network, Inc.; 2009 [cited 2010 Jan 5]. Available from:
http://www.nccn.org/professionals/physician_gls/PDF/antiemesis.pdf.
6. Tramer MR, Carroll D, Campbell FA, et al. Cannabinoids for control of chemotherapyinduced nausea and vomiting: quantitative systematic review. BMJ. 2001 Jul
7;323(7303):16-21.
7. Timpone J, Wright D, Li N, et al. The safety and pharmacokinetics of single-agent and
combination therapy with megestrol acetate and dronabinol for the treatment of HIV
wasting syndrome. AIDS Res Hum Retroviruses. 1997;13(4):305-15.
Page 24 of 52
May 11, 2010 Tennessee PAC
GASTROINTESTINAL AGENTS
RE-REVIEW: MOTILITY AGENTS
BACKGROUND



Metoclopramide stimulates motility of the upper gastrointestinal tract without stimulating
gastric, biliary, or pancreatic secretions though it exact mechanism of action is unclear.
Metoclopramide is FDA approved for the short-term management of symptomatic,
gastroesophageal reflux disease (GERD) in adults who have failed conventional therapy
and for the relief of symptoms associated with acute and recurrent diabetic gastroparesis.
Common adverse events associated with the use of metoclopramide include
restlessness, drowsiness, fatigue and lassitude which occur in approximately 10% of
patients. Extrapyramidal symptoms, manifested primarily as acute dystonic reactions,
occur in approximately 1 in 500 patients treated with the usual adult dosages. There
have been rare reports of an uncommon but potentially fatal symptom complex
sometimes referred to as Neuroleptic Malignant Syndrome (NMS) associated with
metoclopramide.
o Metoclopramide carries a black box warning regarding the risk of tardive
dyskinesia, which is often irreversible. Treatment with metoclopramide for longer
than 12 weeks should be avoided in all but rare cases in which therapeutic benefit is
thought to outweigh the risk of developing tardive dyskinesia.
Use is contraindicated in patients with pheochromocytoma due to the risk of
hypertensive crisis.
o Metoclopramide should not be used whenever stimulation of gastrointestinal
motility might be dangerous, e.g., in the presence of gastrointestinal hemorrhage,
mechanical obstruction, or perforation. It should also not be used in epileptics or
patients receiving other drugs which are likely to cause extrapyramidal reactions,
since the frequency and severity of seizures or extrapyramidal reactions may be
increased.
o Mental depression has occurred in patients with and without prior history of
depression. Metoclopramide should be given to patients with a prior history of
depression only if the expected benefits outweigh the potential risks.
o Parkinsonian-like symptoms have occurred during treatment with
metoclopramide; however these symptoms generally subside within 2 to 3
months following discontinuation. Caution should be used in patients with
preexisting Parkinson’s disease due to the potential for exacerbation.
o A number of clinically significant drug-drug interactions exist with
metoclopramide.
 An increase in the immunosuppressive and toxic effects of cyclosporine
may result with metoclopramide coadministration.
 Metoclopramide may decrease the plasma levels of digoxin by
increasing gastrointestinal motility.
 When taken concomitantly with SSRIs, serotonin syndrome may occur
secondary to inhibition of metoclopramide metabolism. Additionally,
metoclopramide plasma levels may be elevated, increasing the risk of
adverse reactions.
Metoclopramide has been compared directly to a number of other prokinetic agents for
the management of diabetic gastroparesis.
o A systematic review of 36 trials assessed the gastric emptying time and changes
in symptom scores between cisapride, domperidone, erythromycin and
metoclopramide, in patients with delayed gastric emptying, including patients with
diabetic gastroparesis. Gastric emptying time was improved by 44%±11.28%
with erythromycin, by 28.30%±11.58% with domperidone, by 27.1%±12.5% with
cisapride and by 21.4%±14.1% with metoclopramide. Erythromycin (50%±35.4%)
demonstrated a greater improvement in overall symptoms than with domperidone
(47.7%±41%), metoclopramide (40.5%±25.8%) or cisapride (30.8%±27.9%),
P<0.05 for each group.
o

Page 25 of 52
May 11, 2010 Tennessee PAC
GASTROINTESTINAL AGENTS
A Cochrane review has been published comparing a number of medical
treatments in the short term management of reflux esophagitis. Overall,
prokinetic therapy, including metoclopramide, did not demonstrate any significant
benefit vs placebo in reducing persisting esophagitis symptoms (relative risk
[RR], 0.71; 95% confidence interval [CI], 0.46 to 1.1) or healing of esophagitis
(RR, 0.71; 95% CI, 0.46 to 1.1). Additionally, adverse events associated with
prokinetic use did not differ significantly with comparators.
Current guidelines published by the American Gastroenterological Association (AGA)
recommend dietary manipulation and administration of antiemetic and prokinetic agents,
such as erythromycin and metoclopramide for primary treatment of gastroparesis. For
the management of GERD, medications such as proton pump inhibitors and H2-receptor
antagonists have been shown to be more effective than metoclopramide while having a
more favorable safety profile. AGA guidelines do not support the use of metoclopramide
either as monotherapy or as adjunctive therapy for the management of GERD symptoms.
Although not approved for these indications, metoclopramide is one of a number of
agents recommended for low and minimal emetic risk chemotherapy and for
breakthrough emesis by the National Comprehensive Cancer Network.
o

RECOMMENDATION
Metoclopramide, which has both prokinetic and antiemetic properties, is indicated for both diabetic
gastroparesis and symptomatic gastroesophageal reflux. Metoclopramide carries a black box
warning pertaining to the risk of developing tardive dyskinesia, particularly with higher doses and
chronic use. Current guidelines from the AGA recommend the use of motility agents, including
metoclopramide and erythromycin, for treatment of diabetic gastroparesis; however AGA
guidelines do not support the use of metoclopramide either as monotherapy or as adjunctive
therapy for the management of GERD symptoms as proton pump inhibitors and H2-receptor
antagonists have been shown to be more effective with a more favorable safety profile. Although
not FDA approved, metoclopramide is recommended for low and minimal emetic risk
chemotherapy and for breakthrough emesis by the National Comprehensive Cancer Network. It is
recommended at least one metoclopramide product should be available for use.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
RE-REVIEW: MOTILITY AGENTS
PREFERRED
NON-PREFERRED
metoclopramide (compares to Reglan®)
Reglan® (metoclopramide)
Metozolv ODT® (metoclopramide)
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2010.
Accessed March, 2010.
2. Thompson MICROMEDEX on-line © 1974-2010. Accessed March, 2010.
3. Med Metrics. Motility Agents Therapeutic Class Review. March 1, 2010.
4. Sturm A, Holtmann G, Goebell H, Gerken G. Prokinetics in patients with gastroparesis:
a systematic analysis. Digestion. 1999; 60:422-7.
5. Moayyedi P, Santana J, Khan M, Preston C, Donnellan C. Medical treatments in the
short term management of reflux oesophagitis. Cochrane Database of Systematic
Reviews 2007, Issue 2. Art. No.: CD003244. DOI:10.1002/14651858.CD003244.pub2.
6. Parkman HP, Hasler WL, Fisher RS. American Gastroenterological Association.
American Gastroenterological Association Medical Position Statement: diagnosis and
treatment of gastroparesis. Gastroenterology. 2004; 127:1589-91.
7. Kahrilas PJ, Shaheen NJ, Vaezi MF, et al; American Gastroenterological Association.
American Gastroenterological Association Medical Position Statement on the
management of gastroesophageal reflux disease. Gastroenterology. 2008 Oct;
Page 26 of 52
May 11, 2010 Tennessee PAC
GASTROINTESTINAL AGENTS
135(4):1383-91, 1391.e1-5.
8. National Comprehensive Cancer Network. NCCN Clinical practice guidelines in
oncology: Antiemesis v.4.2009 [monograph on the internet]. Jenkintown (PA): National
Comprehensive Cancer Network, Inc.; 2009 [cited 2010 Jan 5]. Available from:
http://www.nccn.org/professionals/physician_gls/PDF/antiemesis.pdf.
Page 27 of 52
May 11, 2010 Tennessee PAC
GASTROINTESTINAL AGENTS
RE-REVIEW: ANTI-DIARRHEALS
BACKGROUND





Most cases of acute diarrhea are caused by bacterial and viral infections, and are selflimited. Noninfectious etiologies become more prevalent in chronic diarrhea, and in
developed countries. Common causes of chronic diarrhea are inflammatory bowel
disease, irritable bowel syndrome, malabsorption syndromes, and chronic infections.
Treatment goals for the management of diarrhea are to regulate the diet; prevent fluid
and electrolyte disturbances; provide symptomatic relief; and treat curable causes.
Antidiarrheal agents included in this review are prescription loperamide, opium tincture,
paregoric, difenoxin/atropine, and diphenoxylate/atropine.
The agents in this class exert their antidiarrheal effects by slowing intestinal motility.
All of the agents in this class are FDA approved for the adjunctive treatment of acute and
chronic diarrhea. Loperamide is also approved for reducing the volume of discharge from
ileostomies.
Loperamide is generally well tolerated with abdominal cramping, constipation, dizziness,
and nausea reported as the most common side effects. Central nervous system and
gastrointestinal side effects are also the most frequently reported adverse events with
difenoxin/atropine, diphenoxylate/atropine, opium tincture, and paregoric.
o Difenoxin/atropine, diphenoxylate/atropine, and loperamide are contraindicated in
children under 2 years of age, and opium tincture is not approved for use in
children. Young children may be predisposed to toxicity and overdosage may
result in severe respiratory depression, coma, and death.
o Difenoxin/atropine, diphenoxylate/atropine, and loperamide are contraindicated in
patients with diarrhea associated with organisms that penetrate the intestinal
mucosa (toxigenic Eschericia coli, Salmonella, Shigella) and
pseudomembranous colitis.
o Opium tincture is contraindicated in patients with severe renal or hepatic
dysfunction, increased intracranial pressure or severe respiratory depression.
o Difenoxin is the principal metabolite of diphenoxylate, which is structurally related
to meperidine. At the usual recommended doses, diphenoxylate produces little or
no opiate effect and does not cause physical dependence; however, high doses
may produce euphoria and physical dependence with chronic administration.
Commercial preparations of difenoxin and diphenoxylate contain a
subtherapeutic amount of atropine to discourage abuse. Morphine is the primary
active ingredient in opium tincture and paregoric. Due to their potential to cause
drug abuse and dependence, difenoxin/atropine (CIV), diphenoxylate/atropine
(CV), opium tincture (CII), and paregoric (CIII) are classified as controlled
substances.
o Loperamide should be used with caution in the treatment of AIDS patients since
cases of toxic megacolon have occurred in AIDS patients with infectious colitis.
o Due to the potential for CNS adverse effects, caution should be used in the
elderly population with difenoxin/atropine, diphenoxylate/atropine, opium tincture,
and paregoric.
o Since atropine slows gastric emptying and gastrointestinal motility, it may
interfere with the absorption of other medications. The potential of atropine (or
atropine-containing products) to cause anticholinergic adverse events may be
increased if it is given with other drugs that have anticholinergic properties.
There are limited published clinical trials evaluating the safety and efficacy of these
antidiarrheal agents for the management of acute or chronic diarrhea. Many of these
agents were introduced to the market before randomized controlled trials were required
for approval.
o One randomized controlled trial compared loperamide to diphenoxylate/atropine
in 83 patients with acute nonspecific diarrhea. No statistically significant
Page 28 of 52
May 11, 2010 Tennessee PAC
GASTROINTESTINAL AGENTS

differences were found between treatment groups in their efficacy and speed of
action in alleviating diarrhea (P values not reported).
o Several small clinical studies reported that loperamide and codeine were more
effective than diphenoxylate/atropine for the symptomatic treatment of chronic
diarrhea.
Current clinical guidelines from the American College of Gastroenterology (ACG), the
World Gastroeneterology Organization, and the Infectious Diseases Society of America
(IDSA) all concur that the antimotility agents are the most effective drugs for symptomatic
treatment of acute diarrhea. Additionally, due to the CNS adverse effects associated with
diphenoxylate and the opiates, all of the guidelines recommend loperamide as the
antimotility agent of choice.
RECOMMENDATION
All of the agents in this class are FDA approved for the adjunctive treatment of acute and chronic
diarrhea and exert their antidiarrheal effects by slowing intestinal motility. Loperamide is generally
well tolerated while CNS adverse effects are frequently reported with difenoxin/atropine,
diphenoxylate/atropine, opium tincture, and paregoric. Due to their potential to cause drug abuse
and dependence, difenoxin/atropine (CIV), diphenoxylate/atropine (CV), opium tincture (CII), and
paregoric (CIII) are classified as controlled substances. Current clinical guidelines concur that the
antimotility agents are the most effective drugs for symptomatic treatment of acute diarrhea and
recommend loperamide as the antimotility agent of choice. Due to its safety profile and lack of
abuse potential, loperamide can be considered a superior agent in this class. Therefore, it is
recommended that at least loperamide should be available for use.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
RE-REVIEW: ANTI-DIARRHEALS
PREFERRED
NON-PREFERRED
diphenoxylate/atropine (compares to
Lomotil® (diphenoxylate/atropine)
Lofene®, Lomotil®, Lonox®)
Motofen® (difenoxin/atropine)
®
Lofene (diphenoxylate/atropine)
opium tincture
Lonox® (diphenoxylate/atropine)
paregoric
loperamide
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2010.
Accessed April, 2010.
2. Thompson MICROMEDEX on-line © 1974-2010. Accessed April, 2010.
3. Jaffe G. A comparison of Lomotil® and Imodium® in acute nonspecific diarrhea. J Int Med
Res. 1977;5(3):195-8. [abstract]
4. DuPont HL. Guidelines on the acute infectious diarrhea in adults. The Practice
Parameters Committee of the American College of Gastroenterolgy. Am J Gastroenterol.
1997 Nov;92(11):1962-75.
5. Hill DR, Ericsson CD, Pearson RD, et al. The practice of travel medicine: guidelines by the
Infectious Diseases Society of America. Clin Infect Dis. 2006 Dec 15;43:1499-539.
6. World Gastroenterology Organization (WGO). WGO practice guideline: acute diarrhea
[guideline on the Internet]. Munich, Germany: World Gastroenterology Organization
(WGO); 2008 Mar. 28 p. [cited 2010 Feb 2]. Available from:
http://www.guideline.gov/summary/summary.aspx?doc_id=12679.
Page 29 of 52
May 11, 2010 Tennessee PAC
GASTROINTESTINAL AGENTS
RE-REVIEW: ANTICHOLINERGICS/ANTISPASMODICS
BACKGROUND

The therapeutic class called the “Anticholinergics/Antispasmodics” encompasses
numerous agents including atropine, dicyclomine, glycopyrrolate, hyoscyamine,
mepenzolate, methscopolamine, propantheline, and scopolamine. Oral agents in this
class are most commonly used for adjunctive treatment of irritable bowel syndrome (IBS).
With the exception of dicyclomine, all of the drugs in this class act as anticholinergic
agents and exert their effect via competitive inhibition of the actions of acetylcholine at
parasympathetic sites in the secretory glands, smooth muscles, and the central nervous
system. Dicyclomine is considered an antispasmodic which is structurally related to the
anticholinergics. While the exact mechanism of action is not known, dicyclomine appears
to act as a nonselective smooth muscle relaxant.
FDA-approved Indications:


Generic
Name
Atropine
Mepenzolate
Methscopolamine
Propantheline
Scopolamine (oral)
Scopolamine
(transdermal)

Infant
colic
I
B
S
Motion
Sickness
Parkinsonism
PUD,
Adjunct
Anticholinesterase
Agents
Poisoning
Prevention
of PONV


(GI, GU)
(GI)








(acute
rhinitis)






Adverse events frequently associated with agents in this class are blurred vision,
constipation, cycloplegia, dry mouth, dry skin, mydriasis, palpitations, and urinary
hesitancy and retention.
o In general, the anticholinergics/antispasmodics are contraindicated in patients
with narrow-angle glaucoma, intestinal atony, myasthenia gravis, obstructive
gastrointestinal diseases, obstructive uropathy, paralytic ileus, severe ulcerative
colitis, and toxic megacolon.
o Agents in this class should be used cautiously in elderly and debilitated patients
and those with autonomic neuropathy, cardiovascular disease, hiatal hernia,
hyperthyroidism, and prostatic hyperplasia.
o The anticholinergics/antispasmodics should be used with caution in patients
receiving concomitant therapy with hypnotics, sedatives, or other psychoactive
substances because of the potential for additive or synergistic central nervous
system effects.
Anticholinergics/antispasmodics have been used principally as adjunctive therapy in the
treatment of IBS and peptic ulcer disease, and scopolamine for the prevention of motion
sickness and postoperative nausea and vomiting. With the exception of scopolamine,
there is limited data to support their use in most conditions.
o In 2008 Ford et al conducted a meta-analysis of 22 trials (N=1,778) evaluating
the effectiveness of antispasmodics for the treatment of IBS. While the authors
concluded that the antispasmodics as a class were more effective than placebo
for the treatment of IBS, only 4 of the 22 trials evaluated drugs that are currently
available in the United States. Three trials were conducted with scopolamine and
1 trial evaluated dicyclomine. Most of the studies in the meta-analysis were
published before 2000 and were considered of poor quality. Overall, 39% of
patients assigned to antispasmodics had persistent symptoms after treatment
compared with 56% of patients allocated to placebo. The RR of symptoms
Page 30 of 52
Reduce
Secretions
(salivary
and
bronchial)

(GI, GU)
Dicyclomine
Glycopyrrolate
Hyoscyamine

Antispas
-modic
May 11, 2010 Tennessee PAC
GASTROINTESTINAL AGENTS



persisting with antispasmodics compared with placebo was 0.68 (95% CI, 0.57 to
0.81). Symptoms persisted in 29% of patients receiving scopolamine compared
with 46% of patients allocated to placebo (RR, 0.63; 95% CI, 0.51 to 0.78;
n=426). To prevent IBS symptoms in 1 patient, 3.5 patients would need to be
treated with scopolamine. Overall, 14% of patients receiving antispasmodics
experienced adverse events compared to 9% receiving placebo.
o A meta-analysis of 14 studies enrolling over 1,000 patients reported that
scopolamine was more effective than placebo in the prevention of motion
sickness symptoms. For the prevention of motion sickness, limited head-to-head
studies suggest that scopolamine was comparable in efficacy to dimenhydrinate,
and was more effective than meclizine and methscopolamine. Scopolamine was
associated with more reports of dry mouth than dimenhydrinate, meclizine, and
methscopolamine.
Guidelines from the American Gastroenterological Association (AGA) and the National
Institute of Health and Clinical Excellence (NICE) state the treatment of IBS should be
based on the nature and severity of symptoms and directed at the predominant
symptoms. The AGA, NICE and American College of Gastroenterology all recommend
anticholinergic/antispasmodic agents for relief of abdominal pain and discomfort
associated with IBS though evidence for long-term efficacy is lacking.
Gycopyrrolate, hyoscyamine, mepenzolate, methscopolamine, propantheline, and oral
scopolamine are FDA approved as adjunct agents in the treatment of peptic ulcer
disease. While these agents have been shown to reduce gastric acid secretion, there are
no conclusive data from well-controlled studies which indicate that these agents
contribute to the healing, decrease the rate of recurrence, or prevent complications of
peptic ulcers. With the development of more effective therapies for the treatment of peptic
ulcer disease, anticholinergics have only limited usefulness in this condition.
In their medical position statement regarding nausea and vomiting, the AGA states that
motion sickness and related disorders are treated primarily with histamine H1 and
cholinergic receptor antagonists (eg, scopolamine). Since oral scopolamine has a short
duration of action and a high incidence of side effects, oral therapy usually has been
reserved for prophylactic treatment of patients exposed to short periods of intense motion
or those who are highly susceptible to motion sickness. Antihistamines or other drugs
have generally been preferred for the prevention of motion sickness in patients with
prolonged exposure to mild to moderate motion. The transdermal delivery of scopolamine
is highly effective for the prevention of motion sickness with a longer duration of action
and fewer side effects than the oral formulation.
RECOMMENDATION
The anticholinergics/antispasmodics are primarily utilized for adjunctive treatment of IBS and
peptic ulcer disease. With the exception of scopolamine, data to support the use of these agents
in most conditions is limited. In addition, adverse effects often limit or prevent their use and these
agents generally have been replaced by other more effective and/or less toxic therapies.
Consensus guidelines state that anticholinergics/antispasmodics may provide short-term relief of
abdominal pain and discomfort in IBS; however, evidence for long-term efficacy is not available.
The anticholinergics/antispasmodics have limited usefulness as adjunctive therapy for peptic ulcer
disease since these agents have not been shown to contribute to the healing, decrease the rate of
recurrence, or prevent complications of peptic ulcers. Scopolamine is commonly used for
prevention of motion sickness and is considered the most effective agent in this class for this
indication. It is recommended that at least three agents in this class should be available for use,
one of which should be oral scopolamine due to its superior data in the prevention of motion
sickness.
COMMITTEE VOTE:
APPROVED
Page 31 of 52
DISAPPROVED
APPROVED with MODIFICATION
May 11, 2010 Tennessee PAC
GASTROINTESTINAL AGENTS
RE-REVIEW: ANTICHOLINERGICS/ANTISPASMODICS
PREFERRED
NON-PREFERRED
Anaspaz® (hyoscyamine)
dicyclomine (compares to Bentyl®)
®
glycopyrrolate (compares to Robinul ,
Bentyl® (dicyclomine)
®
Robinul Forte )
Cantil® (mepenzolate)
®
HyoMax (hyoscyamine)
Levbid® (hyoscyamine)
®
hyoscyamine (compares to Anaspaz ,
Levsin® (hyoscyamine)
®
®
®
®
HyoMax , Hyosyne , Levbid , Levsin ,
methscopolamine (compares to Pamine®, Pamine
®
®
®
NuLev , Symax , Symax Duotab )
Forte®)
®
Hyosyne (hyoscyamine)
Pamine® (methscopolamine)
®
NuLev (hyoscyamine)
Pamine Forte® (methscopolamine)
propantheline
Robinul® (glycopyrrolate)
®
Robinul Forte® (glycopyrrolate)
Symax Fastab (hyoscyamine)
®
Symax-SL (hyoscyamine)
Sal-Tropine® (atropine)
®
Symax-SR (hyoscyamine)
Scopace® (scopolamine)
Symax Duotabs® (hyoscyamine)
Transderm-Scop® CC, QL (scopolamine)
Quantity Limits
Transderm-Scop®
4 patches per 30 days
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
Clinical Criteria for Transderm-Scop®
Prior Authorization for Transderm-Scop will be approved if recipient meets ANY of the following
criteria:
o Trial and failure, or intolerance to, one of the following: meclizine, promethazine,
dimenhydrinate, diphenhydramine, or metoclopramide
o Unable to take oral medication
o Will be in an area/situation for an extended period of time where taking short acting
agents would not be feasible
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2010.
Accessed April, 2010.
2. Thompson MICROMEDEX on-line © 1974-2010. Accessed April, 2010.
3. Med Metrics. Anticholinergics/Antispasmodics Therapeutic Class Review. March 15,
2010.
4. Ford AC, Talley NJ, Spiegel BMR, et al. Effect of fiber, antispasmodics, and peppermint
oil in the treatment of irritable bowel syndrome: systematic review and meta-analysis.
BMJ. 2008 Nov 13:337:a.2313.
5. Dahle E, Offer-Ohlsen D, Lillevold PE, et al. Transdermal scopolamine, oral meclizine,
and placebo in motion sickness. Clin Pharmacol Ther. 1984;36:116-20.
6. Spinks AB, Wasiak J, Villanueva EV, Bernath V. Scopolamine (hyoscine) for preventing
and treating motion sickness. Cochrane Database Syst Rev. 2007 Jul 18;(3):CD002851.
7. American Gastroenterological Association medical position statement: irritable bowel
syndrome. Gastroenterology. 2002;123(6):2105-7.
8. American Gastroenterological Association (AGA) technical review on irritable bowel
syndrome. Gastroenterology. 2002;123(6):2108-131.
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GASTROINTESTINAL AGENTS
9. American College of Gastroenterology IBS Task Force. An evidence-based position
statement on the management of irritable bowel syndrome. Am J Gastroenterology. 2009
Jan;104(supplement 1):S1-S7.
10. National Collaborating Centre for Nursing and Supportive Care. Irritable bowel syndrome
in adults. Diagnosis and management of irritable bowel syndrome in primary care. London
(UK): National Institute for Health and Clinical Excellence (NICE); 2008 Feb. 27 p.
(Clinical guideline; no. 61).
11. American Gastroenterological Association medical position statement: nausea and
vomiting. Gastroenterology. 2001;120(1):261-2.
Page 33 of 52
May 11, 2010 Tennessee PAC
GASTROINTESTINAL AGENTS
RE-REVIEW: 5HT3 RECEPTOR ANTAGONISTS (IBS)
BACKGROUND






Irritable bowel syndrome (IBS) is a functional disorder of the gastrointestinal tract
characterized by abdominal pain, discomfort, and bloating, as well as disturbed bowel
habit. The exact pathogenesis of the disorder is unknown, however; it is believed that
altered gastrointestinal tract motility, visceral hypersensitivity, autonomic dysfunction, and
psychologic factors indicate disturbances within the enteric nervous system which
controls the gastrointestinal system.
Alosetron is a potent and selective 5-HT3 receptor antagonist. 5-HT3 receptors are
located on enteric neurons in the human GI tract as well as other locations and play a
significant role in the control of gastrointestinal motility, sensation, and secretion.
Alosetron is FDA-approved for women with severe diarrhea-predominant IBS who have
chronic symptoms (generally lasting ≥6 months), have had anatomic or biochemical
abnormalities of the gastrointestinal tract excluded, and have not responded adequately
to conventional therapy.
Abdominal pain and constipation are the most frequently reported adverse events
associated with the use of alosetron.
o Alosetron carries a black box warning regarding the risk of infrequent but serious
gastrointestinal adverse reactions. These events, including ischemic colitis and
serious complications of constipation, have resulted in hospitalization, and rarely,
®
blood transfusion, surgery and death. The Prescribing Program for Lotronex
was implemented to help reduce risks of serious gastrointestinal adverse
reactions. Only physicians who have enrolled in the program should prescribe
alosetron based on their understanding of the benefits and risks.
o Use of alosetron is contraindicated in patients with a history of chronic or severe
constipation or sequelae from constipation; intestinal obstruction, stricture, toxic
megacolon, gastrointestinal perforation, and/or adhesions; ischemic colitis,
impaired intestinal circulation, thrombophlebitis, or hypercoagulable state;
Crohn's disease or ulcerative colitis; diverticulitis; and severe hepatic impairment.
o Caution should be used in the elderly population and in patients with mild or
moderate hepatic impairment.
o Concomitant administration of alosetron and fluvoxamine is contraindicated due
to an increased risk of adverse events.
There are no head-to-head studies conducted evaluating alosetron compared to other 5HT3 antagonists or any other IBS treatment. Placebo controlled trials demonstrate that
treatment with alosetron is associated with a significantly greater proportion of patients
reporting adequate relief of IBS pain and discomfort, and improvements in bowel
function.
Guidelines from the American Gastroenterological Association (AGA) and the National
Institute of Health and Clinical Excellence (NICE) state the treatment of IBS should be
based on the nature and severity of symptoms and directed at the predominant
symptoms. Pharmacological treatment options for the management of IBS include
antidepressants, antidiarrheal agents, antispasmodic agents, fiber and laxatives, and
serotonin receptor agonists/antagonists. The AGA states the quality of evidence for
efficacy of 5-HT3 antagonists in the management of IBS is high; however specific
recommendations regarding place in therapy is not addressed in any clinical guidelines.
RECOMMENDATION
Alosetron is a 5-HT3 receptor antagonist that is FDA-approved for use in female patients with
chronic, severe diarrhea-predominant IBS who have not responded to conventional therapy.
Placebo-controlled clinical trial data demonstrate the efficacy of alosetron to reduce pain,
abdominal comfort, urgency, and diarrhea in patients with IBS; however, there are no head-tohead trials that have compared alosetron to other treatment regimens for IBS. Current clinical
guidelines do not specifically address the role of 5-HT3 antagonists in the treatment of IBS.
Page 34 of 52
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Alosetron is the only agent available within this class of medications and due to serious safety
concerns, a boxed warning regarding gastrointestinal adverse events has been assigned to the
agent. In addition, physicians must enroll in a risk management program before prescribing. Due
to safety concerns as well as to ensure patients have not responded to conventional therapy, it is
recommended alosetron be subject to clinical criteria.
COMMITTEE VOTE:
APPROVED
PREFERRED
N/A
DISAPPROVED
APPROVED with MODIFICATION
RE-REVIEW: 5HT3 RECEPTOR ANTAGONISTS (IBS)
NON-PREFERRED
Lotronex® CC, QL (alosetron)
Quantity Limits
Lotronex®
2/day
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
Clinical Criteria for Lotronex®
Prior Authorization for Lotronex will be approved for female patients age ≥18 years upon
documentation of the following:
 Prescriber enrollment in the Promethus Prescribing Program for Lotronex®
(For more information visit: www.lotronex.com or call 1-888-423-5227)
 Diagnosis of severe, diarrhea-predominant, irritable bowel syndrome (IBS)
 Chronic IBS symptoms lasting 6 months or more
 Ruled out anatomic or biochemical abnormalities of the GI tract
 Trial and failure, intolerance or contraindication to two of the following:
o Antispasmodic agents (i.e. dicyclomine, l-hyoscyamine)
o Antidiarrheal agents/opiates (i.e. loperamide, diphenoxylate/atropine, codeine)
o Antidepressants (i.e. Tricyclic antidepressants)
o Bulk producing agents ( i.e. fiber, psyllium)
Initial approval: 8 weeks 12 weeks (3 months) Subsequent approvals: 6 months
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2010.
Accessed April, 2010.
2. Thompson MICROMEDEX on-line © 1974-2010. Accessed April, 2010.
3. Med Metrics. 5-HT3 Receptor Antagonists Therapeutic Class Review. January 12, 2010.
4. Camilleri M, Chey WY, Mayer EA, Northcutt AR, Heath A, Dukes GE et al. A Randomized
Controlled Trial of the Serotonin Type 3 Receptor Antagonist Alosetron in Women With
Diarrhea-Predominant Irritable Bowel Syndrome. Arch Intern Med. 2001;161:1733-40.
5. Chey WD, Chey WY, Heath AT, Dukes GE, Carter EG, Northcutt A et al. Long-Term
Safety and Efficacy of Alosetron in Women with Severe Diarrhea-Predominant Irritable
Bowel Syndrome. Am J Gastroenterol. 2004;99:2195-203.
6. American Gastroenterological Association (AGA). AGA Medical Position Statement:
Irritable Bowel Syndrome. Gastroenterology. 2002;123:2105-7.
7. National Collaborating Centre for Nursing and Supportive Care (NCCNSC) commissioned
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GASTROINTESTINAL AGENTS
by National Institute for Health and Clinical Excellence (NICE). NCCNSC/NICE clinical
practice guideline: Irritable bowel syndrome in adults: diagnosis and management of
irritable bowel syndrome in primary care. 2008 February [cited 2010 January]. Available
from: http://www.nice.org.uk/nicemedia/pdf/IBSFullGuideline.pdf.
8. American College of Gastroenterology. American College of Gastroenterology Task Force
on Irritable Bowel Syndrome: An Evidence-Based Systematic Review on the Management
of Irritable Bowel Syndrome. Am J Gastroenterol. 2009;104(Suppl 1):S1-S35.
Page 36 of 52
May 11, 2010 Tennessee PAC
GASTROINTESTINAL AGENTS
RE-REVIEW: 5-ASA DERIVATIVES, ORAL
BACKGROUND






Inflammatory bowel disease (IBD) is a spectrum of chronic idiopathic inflammatory
intestinal conditions that cause gastrointestinal symptoms that include diarrhea,
abdominal pain, bleeding, and weight loss. The exact cause of IBD is unknown; however
proposed etiologies involve a combination of infectious, genetic, and immunologic
factors. In general, treatment of IBD is centered on agents that work to relieve the
inflammatory process and typically consists of agents that inhibit TNF, antimicrobials,
corticosteroids, immunosuppressive agents, and salicylates. Included in this review are
the oral 5-aminosalicylic acid (5-ASA) derivative preparations which include balsalazide,
mesalamine, olsalazine, and sulfasalazine.
Mesalamine is believed to modulate local chemical mediators of the inflammatory
response, especially leukotrienes, and is also postulated to be a free radical scavenger or
an inhibitor of TNF. Balsalazide and olsalazine are prodrugs of mesalamine.
Sulfasalazine combines a sulfonamide antibiotic (sulfapyridine) and 5-ASA (mesalamine)
in the same molecule. The molecule is cleaved by gut bacteria in the colon releasing
mesalamine, the active component of the medication.
Although the specific FDA approved indications of the oral 5-ASA derivatives vary these
agents are all used in the treatment, induction of remission, and/or maintenance for
®
remission of ulcerative colitis (UC). Of note, sulfasalzine as Azulfidine EN-tab is also
FDA approved for the treatment of rheumatoid arthritis nonresponsive to salicylates and
NSAIDs and for pediatric polyarticular-course juvenile rheumatoid arthritis. Oral
mesalamine preparations are also used off-label for the treatment of Chron’s disease,
Reiter’s disease, and maintenance treatment of chronic ulcerative proctitis. Oral
sulfasalazine preparations are also used off-label in the treatment of radiation-induced
disorder of the gastrointestinal tract.
In general, the oral 5-ASA derivatives are well tolerated. Adverse events with the use of
sulfasalazine are due to the sulfapyridine molecule and commonly include nausea,
heartburn, headache, anemia, skin rashes and decreased sperm count. In rare
instances, hepatitis and kidney inflammation have been associated with the use of
sulfasalazine. Mesalamine has been associated with inducing an acute intolerance
syndrome which is characterized by cramping, acute abdominal pain and bloody
diarrhea, fever, headache, and rash.
o Sulfasalazine is contraindicated in patients allergic to sulfa drugs, with intestinal
or urinary obstruction, or porphyria.
o Cardiac hypersensitivity reactions, such as myocarditis and pericarditis have
been associated with mesalamine-containing medications and thus careful
consideration should be taken prior to giving mesalamine to patients with
predisposing risk factors for such conditions.
o Caution should be used in patients with a history of blood dyscrasias. There have
been reports of fatalities due to hypersensitivity reactions, agranulocytosis and
aplastic anemia secondary to sulfasalazine administration.
o Concomitant administration of sulfasalazine and methotrexate may increase the
risk of methotrexate-induced bone marrow suppression. The anticoagulant effect
of warfarin may be enhanced when in combination with sulfasalazine, increasing
the potential for a hemorrhage.
Green et al compared balsalazide versus sulfasalazine in 57 patients with mild to severe
active UC. A greater number of patients in the balsalazide group (75%) achieved
remission compared to the sulfasalazine group (59%) however the difference did not
reach statistical significance (P=0.19). Fewer patients receiving balsalazide withdrew
from the study compared to those in the sulfasalazine group (2 vs 9; P=0.041).
Olsalazine was compared to mesalamine in 168 patients with mild to moderate active
UC. Remission was achieved in 52.2% of patients receiving olsalazine compared to
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May 11, 2010 Tennessee PAC
GASTROINTESTINAL AGENTS


48.8% of the mesalamine group, a difference that was not statistically significant
(P=0.67).
A meta-analysis including trials of 5-aminosalicylic acid preparations compared to
placebo or sulfasalazine demonstrated that the newer 5- aminosalicylic acid preparations
were no more beneficial than sulfasalazine in maintaining the remission of ulcerative
colitis but were associated with a more favorable side-effect profile.
The goals for the treatment of IBD may relate to resolution of acute inflammatory
processes, resolution of systemic complications, alleviation of systemic manifestations,
maintenance of remission from acute inflammation, or surgical palliation or cure. It is
important to note that none of the drug therapies used in the management of IBD are
curative, and at best work to control the disease process. Current practice parameters
from the American College of Gastroenterology list all of the oral 5-ASA derivatives as
effective therapy for achieving and maintaining remission of UC. Additionally, according
to the ACG the optimal dose and formulation of mesalamine therapy for acute and
maintenance therapy of Crohn's disease remain to be established. None of the currently
available clinical guidelines differentiates between the available agents in this class
based on efficacy, rather the distribution and extent of the disease will dictate the route
and formulation of drug therapy that are most effective.
RECOMMENDATION
The goals for the treatment of IBD include resolution of acute inflammatory processes, resolution
of systemic complications, alleviation of systemic manifestations and maintenance of remission
from acute inflammation. There are currently no curative drug therapies for the management of
IBD, and treatment works only to control the disease process. The oral 5-ASA derivates include
balsalazide, mesalamine, olsalazine, and sulfasalazine which are used in the treatment, induction
of remission, and/or maintenance of remission of ulcerative colitis. Data from clinical trials show
that rates of remission are not significantly different between agents in this class and none of the
currently available clinical guidelines differentiates between the available agents in this class
based on efficacy. Sulfasalazine has been associated with a higher incidence of adverse events
due to the presence of a sulfapyridine molecule. Due to the fact that the distribution and extent of
the disease will dictate the route and formulation of drug therapy that are most effective, it is
recommended that at least two different formulations of mesalamine plus at least one other agent
should be available for use.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
RE-REVIEW: 5-ASA DERIVATIVES, ORAL
PREFERRED
NON-PREFERRED
Asacol® QL (mesalamine)
Apriso® QL (mesalamine)
QL
balsalazide (compares to Colazal)
Asacol HD® QL (mesalamine)
® QL
(olsalazine)
Dipentum
Azulfidine® QL (sulfasalazine)
® QL
(mesalamine)
Lialda
Azulfidine EN® QL (sulfasalazine, delayed release)
® QL
(mesalamine)
Pentasa
Colozal® QL (balsalazide)
QL
sulfasalazine EC (compares to Azulfidine
EN®, Sulfazine EC®)
sulfasalazineQL (compares to Azulfidine®,
Sulfazine®)
Sulfazine EC® QL (sulfasalazine EC)
Sulfazine® QL (sulfasalazine)
Quantity Limits
Apriso®
Asacol®
Asacol HD®
Page 38 of 52
4/day
12/day
6/day
May 11, 2010 Tennessee PAC
GASTROINTESTINAL AGENTS
Azulfidine®, sulfasalazine, Sulfazine®
Azulfidine EN®, sulfasalazine EC, Sulfazine EC®
balsalazide, Colazal®
Dipentum®
Lialda®
Pentasa®
12/day 8/day
12/day 8/day
9/day
12/day 4/day
4/day
250 mg: 20/day 16/day
500 mg: 10/day 8/day
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2010.
Accessed April, 2010.
2. Thompson MICROMEDEX on-line © 1974-2010. Accessed April, 2010.
3. Med Metrics. 5-ASA Derivatives, oral preparations Therapeutic Class Review. March 8,
2010.
4. Kruis W, Brandes JW, Schreiber S, Theuer D, Krakamp B, Schutz E, et al. Olsalazine
versus mesalamine in the treatment of mild to moderate ulcerative colitis [abstract].
Aliment Pharmacol Ther. 1998;12:707-15.
5. Kam L, Cohen H, Dooley C, Rubin P, Orchard J. A comparison of mesalamine suspension
enema and oral sulfasalazine for treatment of active distal ulcerative colitis in adults. Am J
Gastroenterol 1996 Jul;91(7):1338-42.
6. Sutherland L, MacDonald JK. Oral 5-aminosalicylic acid for maintenance of remission in
ulcerative colitis. Cochrane Database of Systemic Reviews 2006, Issue 2. Art. No.:
CD000544. DOI: 10.1002/14651858. CD000544.pub2.
Page 39 of 52
May 11, 2010 Tennessee PAC
GASTROINTESTINAL AGENTS
RE-REVIEW: 5-ASA DERIVATIVES, RECTAL PREPARATIONS
BACKGROUND






Inflammatory bowel disease (IBD) is a spectrum of chronic idiopathic inflammatory
intestinal conditions that cause gastrointestinal symptoms that include diarrhea,
abdominal pain, bleeding, and weight loss. The exact cause of IBD is unknown; however
proposed etiologies involve a combination of infectious, genetic, and immunologic
factors. In general, treatment of IBD is centered on agents that work to relieve the
inflammatory process and typically consists of agents that inhibit TNF, antimicrobials,
corticosteroids, immunosuppressive agents, and salicylates. Currently available 5-ASA
rectal preparations are mesalamine suppositories and mesalamine rectal enemas.
The mechanism of action of mesalamine is not fully understood; however, its action
appears to be topical rather than systemic. Mesalamine is believed to modulate local
chemical mediators of the inflammatory response, especially leukotrienes, and is also
postulated to be a free radical scavenger or an inhibitor of TNF.
Mesalamine enema is FDA-approved for the treatment of active mild to moderate distal
ulcerative colitis, proctosigmoiditis, or proctitis. Mesalamine suppositories are indicated
for the treatment of active ulcerative proctitis.
Adverse events associated with the use of rectal formulations of mesalamine include
dizziness, headache, diarrhea, flatulence, and nausea. Mesalamine is generally well
tolerated with most adverse reactions being mild to moderate. Mesalamine has been
associated with inducing an acute intolerance syndrome which is characterized by
cramping, acute abdominal pain and bloody diarrhea, fever, headache, and rash.
o Cardiac hypersensitivity reactions, such as myocarditis and pericarditis have
been associated with mesalamine-containing medications and thus careful
consideration should be taken prior to giving mesalamine to patients with
predisposing risk factors for such conditions.
o Drug interaction studies have not been conducted with mesalamine suppositories
and no clinically significant drug interactions are reported for mesalamine enema.
There have been no head-to-head trials conducted with the 5-ASA rectal preparations.
One trial was conducted comparing treatment with the mesalamine enema to oral
sulfasalazine in patients with mild to moderate distal ulcerative colitis. In this trial, 94% of
patients receiving rectal mesalamine achieved physician-rated clinical global
improvement scores of either “very much improved” or “much improved” compared to
77% of patients receiving oral sulfasalazine (P value not reported). Additionally, a
significantly greater proportion of patients receiving sulfasalazine therapy reported side
effects compared to the mesalamine group (83% vs 42%; P=0.02).
The goals for the treatment of IBD relate to resolution of acute inflammatory processes,
resolution of systemic complications, alleviation of systemic manifestations, maintenance
of remission from acute inflammation, or surgical palliation or cure. It is important to note
that none of the drug therapies used in the management of IBD are curative, and at best
work to control the disease process. Current guidelines from the American College of
Gastroenterology (ACG) and the British Society of Gastroenterology state that topical
mesalamine agents are considered the first line treatment for active distal ulcerative
colitis. Additionally, the guidelines state that the combination of oral and topical agents is
superior to each agent given as monotherapy. For the maintenance of remission in distal
disease, the ACG states mesalamine suppositories are effective for maintenance of
remission in patients with proctitis and mesalamine enemas are effective in patients with
distal colitis.
RECOMMENDATION
The goals for the treatment of IBD include resolution of acute inflammatory processes, resolution
of systemic complications, alleviation of systemic manifestations and maintenance of remission
from acute inflammation. There are currently no curative drug therapies for the management of
IBD, and treatment works only to control the disease process. Mesalamine enema is FDA-
Page 40 of 52
May 11, 2010 Tennessee PAC
GASTROINTESTINAL AGENTS
approved for the treatment of active mild to moderate distal ulcerative colitis, proctosigmoiditis, or
proctitis. Mesalamine suppositories are indicated for the treatment of active ulcerative proctitis.
Current guidelines from the American College of Gastroenterology (ACG) and the British Society
of Gastroenterology state that topical mesalamine agents are considered the first line treatment for
active distal ulcerative colitis. Head-to-head studies within the class have not been conducted and
none of the current clinical guidelines differentiate among the different preparations in this class.
Given the broader indication of mesalamine enema to treat both proctitis and distal colitis, it is
recommended that at least mesalamine enema should be available for use.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
RE-REVIEW: 5-ASA DERIVATIVES, RECTAL PREPARATIONS
PREFERRED
NON-PREFERRED
Canasa® (mesalamine suppository)
mesalamine kit (compares to Rowasa kit®)
mesalamine enema
Rowasa kit® (mesalamine kit)
sfRowasa® (sulfite-free mesalamine)
Quantity Limits
Canasa®
2/day
Recommend removing the above quantity limits.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2010.
Accessed April, 2010.
2. Thompson MICROMEDEX on-line © 1974-2010. Accessed April, 2010.
3. Med Metrics. 5-ASA Derivatives, Rectal Preparations Therapeutic Class Review. March
8, 2010.
4. Kam L, Cohen H, Dooley C, Rubin P, Orchard J. A comparison of mesalamine suspension
enema and oral sulfasalazine for treatment of active distal ulcerative colitis in adults. Am J
Gastroenterol 1996 Jul;91(7):1338-42.
5. Kornbluth A, Sachar D, Ulcerative Colitis Practice Guidelines in Adults (Update): American
College of Gastroenterology, Practice Parameters Committee. American Journal of
Gastroenterology. 2004;1371-85.
6. Carter, M J, Lobo, A J. Guidelines for the management of inflammatory bowel disease in
adults. Gut.2004;53(V): v1-v16.
Page 41 of 52
May 11, 2010 Tennessee PAC
GASTROINTESTINAL AGENTS
RE-REVIEW: GALLSTONE SOLUBILIZING AGENTS
BACKGROUND








Ursodiol, also referred to as ursodeoxycholic acid (UDCA), is a naturally occurring bile
acid that suppresses hepatic synthesis and secretion of cholesterol, and inhibits intestinal
absorption of cholesterol.
Ursodiol capsules are currently FDA approved for the prevention and dissolution of
gallstones while the tablet formulations are currently approved for primary biliary
cirrhosis.
Multiple adverse events have been reported with the use of ursodiol including diarrhea,
abdominal pain, constipation, nausea and vomiting, dizziness, asthenia, headache, upper
respiratory infections and weight gain.
o Patients with calcified cholesterol stones, radiopaque stones, or radiolucent bile
pigment stones are not candidates for ursodiol therapy.
o There are no clinically significant drug interactions reported with ursodiol.
However, bile acid sequestrants and aluminum–based antacids are thought to
interfere with the action of ursodiol by reducing its absorption.
The use of UDCA for the dissolution of gallstones was analyzed in a double-blind,
randomized controlled trial, including 154 symptomatic patients. No significant difference
in gallstone dissolution rate was noted at 6 months between the use of UDCA alone
(47%) or in combination with chenodeoxycholic acid (44%), a second bile acid. Similar
results were also found after 12 months of therapy (59% of the UDCA group vs 53% of
the combination group). Additionally, complete dissolution was reported in 28% of UDCA
patients and 30% of combination patients, this difference also failed to reach statistical
significance.
A large trial (N=1,004) compared three dosage regimens of UDCA to placebo in gallstone
prevention in obese patients experiencing rapid weight loss secondary to participation in
a very-low-calorie diet program. The rate of gallstone development was significantly
higher in the placebo group compared to all doses of UDCA (28% vs 8% of the UDCA
300 mg/day group, 3% of the UDCA 600 mg/day group and 2% of the UDCA 1,200
mg/day group). A significant difference was also detected between UDCA 600 mg and
UDCA 300 mg (P=0.05) as well as UDCA 1,200 mg and UDCA 300 mg (P<0.01).
Meta-analyses of placebo-controlled studies involving over 1,500 patients with primary
biliary cirrhosis failed to find a significant advantage of UDCA in overall mortality, liverrelated mortality and liver transplant or in manifestation of liver disease.
Cholecystectomy is standard treatment for gallstones in patients who are either
symptomatic or at high risk of developing complications. Ursodiol is generally reserved
for patients with gallstones who are symptomatic or at high risk for complications, but
require an alternative to surgery. The dissolution of gallstones with ursodiol is limited by
the rate of recurrence and the fact that symptom relief may not occur for 3 to 6 weeks
and results may take up to 6 to 24 months. Clinical trials have shown that ursodiol is
effective as prophylactic therapy in the setting of rapid weight loss when compared to
placebo.
The American Association for the Study of Liver Diseases (AASLD) practice guidelines
recommends UDCA for patients with primary biliary cirrhosis who have abnormal liver
enzymes regardless of histologic stage.
RECOMMENDATION
Ursodiol is a naturally occurring bile acid that suppresses hepatic synthesis and secretion of
cholesterol, and inhibits intestinal absorption of cholesterol. Ursodiol capsules are FDA approved
for the treatment of gallstones; however, use is generally reserved for patients with gallstones who
are symptomatic or at high risk for complications, but require an alternative to surgery. Ursodiol
capsules are also approved for prophylaxis against gallstone formation in obese patients
experiencing rapid weight loss and clinical trials have shown its effectiveness in this setting.
Ursodiol tablets are indicated for the treatment of patients with primary biliary cirrhosis and AASLD
Page 42 of 52
May 11, 2010 Tennessee PAC
GASTROINTESTINAL AGENTS
practice guidelines recommend ursodiol for patients with primary biliary cirrhosis who have
abnormal liver enzymes regardless of histologic stage. It is recommended that at least one
ursodiol formulation should be available for use.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
RE-REVIEW: GALLSTONE SOLUBILIZING AGENTS
PREFERRED
NON-PREFERRED
Actigall® QL
ursodiolQL (compares to Actigall®, Urso®,
®
Urso Forte )
Urso® QL
Urso Forte® QL
Quantity Limits
Actigall® (ursodiol capsules)
Urso® (ursodiol tablets)
Urso Forte® (ursodiol tablets)
3/day
3/day
2/day
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2010.
Accessed March, 2010.
2. Thompson MICROMEDEX on-line © 1974-2010. Accessed March, 2010.
3. Med Metrics. Gallstone Solubilizing Agents Therapeutic Class Review. March 1, 2010.
4. Petroni ML, Jazrawi RP, Pazzi P, Lanzani A, Zuin M, Pigozzi MG, et al. Ursodeoxycholic
acid alone or with chenodeoxycholic acid for dissolution of cholesterol gallstones: a
randomized multicentre trial. Aliment Pharmacol Ther. 2001; 15:123-8.
5. Shiffman ML, Kaplan GD, Brinkman-Kaplan V, Vickers F. Prophylaxis against gallstone
formation with ursodeoxycholic acid in patients participating in a very-low-calorie diet
program. Ann Intern Med. 1995; 122:899-905.
6. Goulis J, Leandro G, Burroughs AK. Randomized controlled trials of ursodeoxycholicacid therapy for primary biliary cirrhosis: a meta-analysis. The Lancet. 1999; 354:105360.
7. Gong Y, Huang ZB, Christensen E, Gluud C. Ursodeoxycholic acid for primary biliary
cirrhosis. Cochrane Database of Systematic Reviews 2008, Issue 3. Art. No.:
CD000551. DOI: 10.1002/14651858.CD000551.pub2.
8. Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, Heathcote EJ, American
Association for Study of Liver Diseases. Primary biliary cirrhosis. Hepatology. 2009;
50(1):291-308.
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GASTROINTESTINAL AGENTS
RE-REVIEW: ULCER PROTECTANTS
BACKGROUND
 The ulcer protectants therapeutic class consists of two agents, misoprostol and
sucralfate.
 Misoprostol is a synthetic prostaglandin and increases bicarbonate and mucus production
within the gastric mucosa inhibiting gastric acid secretion.
 Sucralfate forms an ulcer-adherent complex that locally covers an ulcer site and protects
it from damage by acid, pepsin and bile salts.
 Misoprostol is FDA approved for reducing the risk of nonsteroidal anti-inflammatory drug
(NSAID)–induced gastric ulcers in patients at high risk of complications or patients at high
risk of developing gastric ulceration. Sucralfate is FDA approved for the short-term
treatment (up to 8 weeks) of active duodenal ulcer and maintenance therapy for duodenal
ulcer patients once the ulcer has healed.
 The most common adverse effect with sucralfate is constipation. Misoprostol’s adverse
effects include abdominal pain, nausea, diarrhea, and flatulence.
o
Misoprostol carries a black box warning regarding its abortifacient properties.
Misoprostol administration to women who are pregnant can cause abortion,
premature birth, or birth defects.
o
Misoprostol is contraindicated during pregnancy due to its abortifacient
properties.
o
Caution should be used when administering misoprostol in patients with cerebral
vascular or coronary artery disease.
o
There is an increased risk of aluminum accumulation and toxicity with the use of
sucralfate in patients with chronic renal failure and on dialysis.
o
There are no clinically significant drug interactions reported with misoprostol.
Sucralfate has the potential to alter the binding and absorption of other
medications if administered simultaneously.

In a large randomized, double-blind, placebo-controlled trial (N=8843), adult patients
receiving continuous non-steroidal anti-inflammatory drug (NSAID) therapy who were
given misoprostol, demonstrated a 40% reduction in the risk of developing serious upper
gastrointestinal complications compared to placebo (P=0.049).

In a Cochrane review, misoprostol use was associated with a significant reduction in the
risk of developing gastric ulcer in patients on chronic NSAID therapy compared to
placebo and standard dose ranitidine. This review also found that prophylaxis with proton
pump inhibitors was comparable to misoprostol.

Archimandritis et al conducted a randomized, double-blind study in 165 patients with
duodenal ulcer comparing sucralfate to ranitidine in the rate of healing of ulcer and
symptom relief. Sucralfate achieved ulcer healing in 73.5% of patients versus 63.3% of
ranitidine patients at 4 weeks. At 8 weeks, a cumulative ulcer healing rate of 89% in
patients receiving sucralfate and 84.8% of patients on ranitidine was noted (P values not
reported). No difference was reported in the rate of symptom relief or side effects.

The American College of Gastroenterology recommends either misoprostol or a proton
pump inhibitor (PPI) as appropriate therapy for the prevention of NSAID-related ulcer
complications in patients at moderate and high risk for ulcers. However, the use of
misoprostol may be limited by its side effect profile which includes diarrhea and
abdominal cramping.

Current clinical practice considers antacids, H2-receptor antagonists, PPIs and sucralfate
as conventional antiulcer therapy, and note that sucralfate and H2-receptor antagonist
therapy have similar efficacy. Although sucralfate has relatively few adverse effects it
does interact with numerous medications.
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GASTROINTESTINAL AGENTS
RECOMMENDATION
Gastric and duodenal ulcers in the gastrointestinal tract are potential outcomes from use of
NSAIDs and infections with H. Pylori. The two ulcer protectants, misoprostol and sucralfate, are
indicated to treat or prevent ulcers at separate regions of the gastrointestinal tract. The American
College of Gastroenterology recommends either misoprostol or a proton pump inhibitor (PPI) as
appropriate therapy for the prevention of NSAID-related ulcer complications in patients at
moderate and high risk for ulcers. However, the use of misoprostol is limited by its side effect
profile and abortifacient properties. Sucralfate is not specifically included in the clinical guidelines
but is also considered a conventional antiulcer treatment; it is associated with fewer adverse
effects but has increased drug interactions. Clinical trials have demonstrated efficacy of both
agents compared to placebo and other anti-ulcer agents. Therefore, it is recommended that at
least one anti-ulcer agent be available for use.
COMMITTEE VOTE:
APPROVED
PREFERRED
misoprostol
sucralfate
DISAPPROVED
APPROVED with MODIFICATION
RE-REVIEW: ULCER PROTECTANTS
NON-PREFERRED
Carafate® (sucralfate)
Cytotec® (misoprostol)
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2010.
Accessed April, 2010.
2. Thompson MICROMEDEX on-line © 1974-2009. Accessed April, 2010.
3. MedMetrics. Ulcer Protectants class review. 02/01/2010.
4. Lanza FL, Chan FKL, Quigley EMM, the Practice Parameters Committee of the
American College of Gastroenterology. Guidelines for prevention of NSAID-related ulcer
complications. Am J Gastroenterol. 2009;104:728-38.
5. Bhatt DL, Scheiman J, Abraham NS, Antman EM, Chan FKL, Furberg CD, et al.
ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the Gastrointestinal
Risks of Antiplatelet Therapy and NSAID Use. Am J Gastroenterol. 2008;103:2890-907.
6. Gastrointestinal drugs 56:00, Antiulcer agents and acid suppressants 56:28, Protectants
56:28:32. In: McEvoy GK, editor; American Hospital Formulary Service. AHFS drug
information 2010 [monograph on the Internet]. Bethesda (MD): American Society of
Health-System Pharmacists; 2010 [cited 2010 Jan 8]. Available from:
http://online.statref.com.
7. Ramakrishnan K, Salinas RC. Peptic ulcer disease. Am Fam Physician. 2007;76:100512.
8. Management of duodenal ulcers in patients infected with Helicobacter pylori. In: Basow
D, editor. UpToDate [database on the Internet]. Waltham (MA): UpToDate; 2010 [cited
2010 Jan 28]. Available from: http://www.utdol.com/utd/index.do.
9. Silverstein FE, Graham DY, Senior JR, Davies HW, Struthers BJ, Bittman RM, et al.
Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid
arthritis receiving nonsteroidal anti-inflammatory drugs. Ann Intern Med. 1995;123:2419.
10. Rostom A, Dube C, Wells GA, Tugwell P, Welch V, Jolicoeur E, McGowan JL.
Prevention of NSAID-induced gastroduodenal ulcers. Cochrane Database of Systematic
Reviews 2002, Issue 4. Art. No.: CD002296. DOI:10.1002/14651858.CD002296.
Page 45 of 52
May 11, 2010 Tennessee PAC
GASTROINTESTINAL AGENTS
RE-REVIEW: COMBINATION AGENTS FOR H. PYLORI
BACKGROUND
 Helicobacter pylori (H pylori), a gram-negative spiral bacteria, has been found to cause
gastric and duodenal ulcers and has been linked to the development of gastric cancers.
Eradication of H pylori reduces the risk of duodenal ulcer recurrence. There are currently
three combination products available for the treatment/eradication of H pylori in patients
with duodenal disease: amoxicillin/clarithromycin/lansoprazole, bismuth subcitrate
potassium/metronidazole/tetracycline, and bismuth
subsalicylate/metronidazole/tetracycline.
 Lansoprazole acts to inhibit gastric acid secretion from gastric parietal cells.
 Amoxicillin, clarithromycin, metronidazole, and tetracycline all exhibit anti-microbial
actions against H pylori.
 FDA indications
Agent
Amoxicillin,
clarithromycin and
lansoprazole
Bismuth subcitrate
potassium/ metronidazole/
tetracycline
Bismuth subsalicylate,
metronidazole
and tetracycline

The most common adverse effects seen with the combination agents for H pylori include
diarrhea, headache and taste perversion.
o
o
o
Metronidazole carries a black box warning regarding its potential carcinogenic
effect in mice and rats and to avoid any unnecessary use.
Bismuth subcitrate potassium/metronidazole/tetracycline and bismuth
subsalicylate/metronidazole/tetracycline are contraindicated in pregnant or
nursing women; pediatric patients; patients with renal or hepatic impairment due
to the salicylate properties of bismuth.
To reduce the development of drug-resistant bacteria and maintain the
effectiveness of these combination products and other antibacterial drugs, the
agents should be used only to treat or prevent infections that are proven or
strongly suspected to be caused by susceptible bacteria.
o
Use of the combination products to eradicate H pylori may result in
superinfections with mycotic or bacterial pathogens, including Clostridium
difficile.
o
Significant Drug-Drug Interactions:


Indication
Treatment of patients with H pylori infection and
duodenal ulcer disease (active or one-year history of a
duodenal ulcer) to eradicate H pylori.
Combination therapy with omeprazole for the
treatment of patients with H pylori infection and
duodenal ulcer disease (active or history of within the
past 5 years) to eradicate H pylori.
Combination therapy with a histamine H2-receptor
antagonist for the treatment of patients with H pylori
infection and duodenal ulcer disease (active or history
of duodenal ulcer) to eradicate H pylori.
Clarithromycin should not be used concomitantly with cisapride,
pimozide, astemizole, terfenadine, ergotamine or dihydroergotamine due
to the increased risk of QT prolongation and ventricular arrhythmias,
including ventricular tachycardia and torsades de pointes.
Clinical trials have demonstrated that these products are effective for their approved
indications. Head-to-head trials and meta-analyses have reported that bismuth-based
quadruple therapy was at least as effective as standard triple therapy for the eradication
of H pylori. There are no current head to head comparisons of differing quadruple based
regimens. Additionally, there are no studies that have demonstrated that use of these
Page 46 of 52
May 11, 2010 Tennessee PAC
GASTROINTESTINAL AGENTS

combination products are more efficacious or improve clinical outcomes when compared
to administration of the individual components as separate prescriptions.
o Kearney et al compared regimens of bismuth
subsalicylate/metronidazole/tetracycline and either cimetidine or famotidine
regimen (BMT-H2) to bismuth
subsalicylate/metronidazole/tetracycline/lansoprazole (BMT-PPI) or
metronidazole/lansoprazole/clarithromycin (MLC) in patients with positive tests
for H. Pylori. Primary endpoint was cure rate of H. Pylori infection. The intent-totreat cure rates for BMT-H2, BMT-PPI, and MLC were 81%, 87% and 90%,
respectively. The corresponding per-protocol cure rates were 84%, 91% and
92%. Comparison of the cure rates between each treatment groups found no
significant differences (all P>0.05). The side-effect profile for the 3 treatment
groups revealed no significant differences in the frequency of the most common
side effects, diarrhea and constipation (P value not reported).
o Magaret et al compared regimens of lansoprazole/amoxicillin/clarithromycin to
lansoprazole/bismuth subsalicylate/metronidazole/tetracycline in patients who
had failed prior treatment for H. Pylori tests (N=240). Primary endpoint was
eradication rates. Per-protocol eradication rates for patients on triple therapy and
quadruple therapy were 82% and 80%, respectively (P=0.85). Intention-to-treat
eradication rates for triple and quadruple therapy were 72% and 65%,
respectively (P=0.63). There were no statistically significant differences between
triple and quadruple therapy.
o Ulmer et al conducted a meta analysis (79 trials, N=8383) comparing H. Pylori
triple therapy with lansoprazole, omeprazole, or pantoprazole, treatment
durations were 7 days. Primary endpoint was H. Pylori eradication rates.
Eradication rates for all therapies were 71.9%-83.9% in the intention-to-treat
population and 78.5%-91.2% for the per-protocol analysis. Pooled data analysis
indicated that lansoprazole, omeprazole, or pantoprazole-based therapies are
comparable in H pylori eradication.
National and international consensus guidelines from the American College of
Gastroenterology and the European Helicobacter pylori Study Group recommend triple
therapy with clarithromycin, a proton-pump inhibitor (PPI), and amoxicillin or
metronidazole as a treatment of choice for the eradication of H pylori. Another first-line
option is quadruple therapy with histamine (H2)-receptor antagonist or PPI, bismuth,
metronidazole and tetracycline. Also recommended triple based therapy duration is 14
days and quadruple based therapy duration 10 to 14. Consensus guidelines do not give
preference to one PPI over another for the eradication of H pylori. The American College
of Gastroenterology states that currently available PPIs perform comparably when used
in triple therapy regimens
RECOMMENDATION
H pylori infections have been found to cause gastric and duodenal ulcers and have been linked to
the development of gastric cancers. Combination agents of proton pump inhibitors, antibiotics, and
bismuth are utilized to eradicate infections. Clinical trials have demonstrated efficacy and
demonstrated quadruple therapy was as effective as standard triple therapy. Consensus
guidelines from the American College of Gastroenterology and the European Helicobacter pylori
Study Group recommend triple therapy with clarithromycin, a proton-pump inhibitor (PPI), and
amoxicillin or metronidazole, and quadruple based therapy with histamine (H2)-receptor antagonist
or PPI, bismuth, metronidazole and tetracycline as an alternative first line treatment. Therefore it is
recommended that at least one combination agent for H. Pylori is available for use. However, to
ensure appropriate use and duration of therapy, it is recommended all agents in the class are
subject to clinical criteria.
COMMITTEE VOTE:
APPROVED
Page 47 of 52
DISAPPROVED
APPROVED with MODIFICATION
May 11, 2010 Tennessee PAC
GASTROINTESTINAL AGENTS
RE-REVIEW: COMBINATION AGENTS FOR H. PYLORI
PREFERRED
NON-PREFERRED
Helidac® CC,QL (bismuth
Prevpac® CC,QL (amoxicillin/clarithromycin/lansoprazole)
subsalicylate/metronidazole/
Pylera® CC,QL (bismuth subcitrate/ metronidazole/tetracycline)
tetracycline)
Clinical Criteria for Combination agents for H. Pylori
Approval will be granted based on documentation of:
o Diagnosis of Helicobacter Pylori (H. Pylori) infection AND
o Documentation of recent positive H. Pylori test
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
Quantity Limits
Prevpac® 1 box/RX
Helidac® 1 box/RX
Pylera® 120 caps/RX
*up to 2 courses of therapy per year
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2010.
Accessed April, 2010.
2. Thompson MICROMEDEX on-line © 1974-2010. Accessed April, 2010.
3. MedMetrics. Combination products for helicobacter pylori class review. 01/15/2010.
4. Chey WD, Wong BCY and the Practice Parameters Committee of the American College
of Gastroenterology. American College of Gastroenterology guideline on the
management of Helicobacter pylori infection. Am J Gastroenterol. 2007;102:1808-25.
5. Malfertheiner P, Megraud F, O’Morain C, et al and the European Helicobacter Study
Group (EHSG). Current concepts in the management of Helicobacter pylori infection:
the Maastricht III Consensus Report. Gut. 2007 Jun;56(6):772-81.
6. Kearney DJ, Brousal A. Treatment of Helicobacter pylori infection in clinical practice in
the United States. Dig Dis Sci. 2000;45(2):2765-71.
7. Magaret N, Burm M, Faigel D, Kelly C, Peterson W, Fennerty MB. A randomized trial of
lansoprazole, amoxicillin, and clarithromycin versus lansoprazole, bismuth,
metronidazole and tetracycline in the retreatment of patients failing initial Helicobacter
pylori therapy. Dig Dis. 2001;19:174-8.
8. Ulmer HJ, Beckerling A, Gatz G. Recent use of proton-pump inhibitor-based triple
therapies for the eradication of H pylori: a broad data review. Helicobacter.
2003;8(2):95-104.
9. Chey WD, Wong BCY and the Practice Parameters Committee of the American College
of Gastroenterology. American College of Gastroenterology guideline on the
management of Helicobacter pylori infection. Am J Gastroenterol. 2007;102:1808-25.
10. Malfertheiner P, Megraud F, O’Morain C, et al and the European Helicobacter Study
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GASTROINTESTINAL AGENTS
Group (EHSG). Current concepts in the management of Helicobacter pylori infection:
the Maastricht III Consensus Report. Gut. 2007 Jun;56(6):772-81.
Page 49 of 52
May 11, 2010 Tennessee PAC
GASTROINTESTINAL AGENTS
RE-REVIEW: SALIVA STIMULATING AGENTS
BACKGROUND





Cevimeline and pilocarpine are cholinergic agents that bind to muscarinic receptors
causing increased secretion by exocrine glands resulting in salivation, as well as
lacrimation and sweat production.
Both of these agents are FDA approved for the treatment of dry mouth, or xerostomia,
associated with Sjögren's syndrome. Pilocarpine is additionally FDA approved for
patients with salivary gland hypofunction caused by radiotherapy for cancer of the head
and neck.
The most common adverse effects seen with the saliva stimulating agents include
diarrhea, excessive sweating, nausea, and headache.
o Cevimeline and pilocarpine are contraindicated in patients with uncontrolled
asthma; the agents can potentially increase airway resistance, bronchial smooth
muscle tone, and bronchial secretions.
o Cevimeline and pilocarpine are contraindicated in patients with acute iritis and
narrow-angle glaucoma, agents can cause miosis.
o Saliva stimulants may have dose-related central nervous system effects. Caution
should be used when treating patients with underlying cognitive or psychiatric
disturbances.
o The saliva stimulating agents can potentially alter cardiac conductions and/or
heart rate; caution should be used in patients with significant cardiovascular
disease.
o There are no significant drug-drug interactions.
Clinical trials have demonstrated efficacy of saliva stimulating agents when compared to
placebo. There are currently no clinical studies available directly comparing cevimeline
and pilocarpine.
o Petrone et al evaluated the safety and efficacy of cevimeline in adult patients with
salivary gland dysfunction secondary to Sjögren's syndrome and found that
cevimeline 30 mg three times a day was associated with statistically significant
improvements in dry mouth over placebo (66% vs 37%; P=0.0004) and an
increased salivary flow rate (P=0.007).
o When compared to placebo a greater proportion of patients with Sjögren's
syndrome receiving pilocarpine 5 mg four times a day demonstrated a significant
global improvement in dry mouth in two randomized trials (61.3% vs 31.1%;
P≤0.001 and 69.6% vs 23.8%; P=0.0032). Significant improvements in
secondary outcomes such as mouth comfort, mouth dryness and the ability to
sleep due to a reduction in nocturnal fluid ingestion were noted in both trials.
o A systematic review of 3 randomized controlled trials in patients with radiation
induced salivary gland dysfunction showed that pilocarpine was more effective
than placebo, and at least as effective as artificial saliva in improving the
sensation of dryness of the mouth. Forty-two percent to 51% of patients
responded and the time to response was up to 12 weeks (no P Values reported).
Treatment of xerostomia includes good oral hygiene, salivary stimulation and
replacement of salivary secretions. The saliva stimulating agents have been shown to
improve subjective and objective signs and symptoms of xerostomia in patients with
Sjögren's syndrome and with xerostomia associated with salivary gland hypofunction
caused by radiotherapy for cancer of the head and neck. The National Comprehenisve
Cancer Network (NCCN) Task Force Report on the Management of Mucositosis includes
both the saliva stimulating agents as treatment options along with over the counter (OTC)
products for relief of xerostomia associated with salivary gland hypofunction caused by
radiotherapy for cancer of the head and neck. Scottish clinical guidelines for the
Management of Head and Neck Cancer recommend the use of pilocarpine to alleviate
symptoms from radiation-induced xerostomia.
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GASTROINTESTINAL AGENTS
RECOMMENDATION
The saliva stimulating agents have been shown to improve subjective and objective signs and
symptoms of xerostomia associated with Sjögren's syndrome and radiation utilized in various
malignancies. The saliva stimulating agents are cholinergic agents that do have systemic adverse
effects when compared to other treatment alternatives, such as OTC saliva substitutes. Limited
clinical trials have demonstrated efficacy of saliva stimulating agents when compared to placebo
and there are no current head to head comparisons of the available agents. Clinical oncology
guidelines include prescription and OTC saliva stimulating agents for treatment of radiation
induced xerostomia. Therefore, it is recommended that at least one saliva stimulating agent is
available for use. However, due to the relatively high cost of saliva stimulating agents and their
potential to cause systemic adverse effects, it is recommended that all agents in this class are
subject to clinical criteria.
COMMITTEE VOTE:
APPROVED
DISAPPROVED
APPROVED with MODIFICATION
RE-REVIEW: SALIVA STIMULATING AGENTS
PREFERRED
NON-PREFERRED
pilocarpine QL, CC (compares to Salagen®)
Evoxac® QL, ST, CC (cevimeline)
Salagen® QL, CC (pilocarpine)
CLINICAL CRITERIA
Approval will be granted upon documentation of
1. Diagnosis of Sjögren's syndrome OR radiation-induced xerostomia
2. Trial and failure or intolerance to one OTC saliva substitute
QUANITY LIMITS
Evoxac 90 tab/30 days
Pilocarpine 60 tab/30 days 90 tab/30 days
Salagen 60 tab/30 days 90 tab/30 days
References
1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2010.
Accessed April, 2010.
2. Thompson MICROMEDEX on-line © 1974-2010. Accessed April, 2010.
3. MedMetrics. Saliva Stimulating class review. 02/01/2010.
4. Petrone D, Condemi JJ, Fife R, Gluck O, Cohen S, Dalgin P. A double-blind,
randomized, placebo-controlled study of cevimeline in Sjögren’s syndrome patients with
xerostomia and keratoconjunctivitis sicca. Arthritis & Rheumatism. 2002; 46(3):748-54.
5. Vivino FB, Al-Hashimi I, Khan Z, LeVeque FG, Salisbury PL, Tran-Johnson TK, et al.
Pilocarpine tablets for the treatment of dry mouth and dry eye symptoms in patients with
Sjögren syndrome: A randomized, placebo-controlled, fixed-dose, multicenter trial. Arch
Intern Med. 1999; 159:174-81.
6. Wu C-H, Hsieh S-C, Lee K-L, Li K-J, Lu M-C, Yu C-L. Pilocarpine hydrochloride for the
treatment of xerostomia in patients with Sjögren’s syndrome in Taiwan-A double-blind,
placebo-controlled trial. J Formos Med Assoc. 2006; 105:796-803.
7. Davies AN, Shorthose K. Parasympathomimetic drugs for the treatment of salivary
gland dysfunction due to radiotherapy. Cochrane Database of Systematic Reviews
2007, Issue 3. Art. No.: CD003782. DOI:10.1002/14651858.CD003782.pub2.
8. Scottish Intercollegiate Guidelines Network (SIGN). Diagnosis and management of head
and neck cancer. A national clinical guideline. Edinburgh (Scotland): Scottish
Intercollegiate Guidelines Network (SIGN); 2006 Oct. 90 p. (SIGN publication; no. 90).
9. Besinger W, Schubert M, Brizel D, et al. NCCN Task Force Report: Prevention and
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GASTROINTESTINAL AGENTS
Management of Mucositosis in Cancer. J Natl Compr Can Netw. 2008 Jan; 6 Suppl 1;
S1-S21.
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